Substituted sulfonamide compounds

ABSTRACT

Substituted sulfonamide compounds corresponding to the formula I 
                         
wherein m, n, p, Q, R 1 , R 2 , R 3 , R 4 , X, Y and Z have the respective meanings defined herein, pharmaceutical compositions containing such compounds, a process for their preparation, and the use of such compounds for the treatment and/or inhibition of pain and other conditions mediated by bradykinin receptor 1 (B1R) and/or bradykinin receptor 2 (B2R).

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority from U.S. provisional patent application No. 61/021,809, filed Jan. 17, 2008 and from European patent application no. EP 08000840, also filed Jan. 17, 2008, the entire disclosures of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

The present invention relates to substituted sulfonamide compounds, processes for their preparation, medicaments containing these compounds, and the use of substituted sulfonamide compounds for the preparation of pharmaceutical compositions.

In contrast to the constitutive expression of the bradykinin 2 receptor (B2R) the bradykinin 1 receptor (B1R) is not expressed, or is only weakly expressed in most tissues. However, the expression of B1R can be induced in various cells. For example, in the course of inflammatory reactions there is a rapid and pronounced induction of B1R on neuronal cells but also on various peripheral cells such as fibroblasts, endothelial cells, granulocytes, macrophages and lymphocytes. In the course of inflammatory reactions there is thus a switch from a B2R to a B1R dominance on the involved cells. The cytokines interleukin-1 (IL-1) and tumour necrosis factor alpha (TNFα) (Passos et al. J. Immunol. 2004, 172, 1839-1847) are significantly involved in this up-regulation. After activation with specific ligands, B1R-expressing cells can then themselves secrete inflammation-promoting cytokines such as IL-6 and IL-8 (Hayashi et al. Eur. Respir. J. 2000, 16, 452-458). This leads to the inflow of further inflammatory cells, e.g. neutrophilic granulocytes (Pesquero et al. PNAS 2000, 97, 8140-8145). Via these mechanisms the bradykinin B1R system can contribute to the chronic condition of diseases. This is confirmed by a number of animal experiment investigations (reviews in Leeb-Lundberg et al., Pharmacol Rev. 2005, 57, 27-77 and Pesquero et al., Biol. Chem., 2006, 387, 119-126). An enhanced expression of B1R is also found in humans, for example on enterocytes and macrophages in the affected tissue of patients suffering from inflammatory intestinal diseases (Stadnicki et al. Am. J. Physio. Gastrointest. Liver Physiol. 2005, 289, G361-366) and on T lymphocytes of patients suffering from multiple sclerosis (Pratet et al., Neurology, 1999, 53, 2087-2092) or an activation of the bradykinin B2R-B1R system during infections with Staphylococcus aureus (Bengtson et al., Blood 2006, 108, 2055-2063). Infections with Staphylococcus aureus are responsible for clinical conditions ranging from surface infections of the skin up to septic shock.

Due to the pathophysiological relationships outlined above, there is a great therapeutic potential for the use of B1R antagonists in acute and in particular chronic-inflammatory diseases. These include diseases of the respiratory tract (bronchial asthma, allergies, COPD (chronic obstructive pulmonary disease), cystic fibrosis, etc.), inflammatory intestinal diseases (ulcerative colitis, CD (Crohn's disease), etc.), neurological diseases (multiple sclerosis, neurodegeneration, etc.), inflammations of the skin (atopic dermatitis, psoriasis, bacterial infections, etc.) and mucous membranes (M. Behcet, pelvitis, prostatitis), rheumatic diseases (rheumatoid arthritis, osteoarthritis, etc.), septic shock, and reperfusion syndrome (after heart attacks and strokes).

In addition the bradykinin (receptor) system is also involved in the regulation of angiogenesis (potential as an angiogenesis inhibitor in cancer and also macular degeneration of the eye) and B1R knockout mice are protected against the danger of becoming overweight due to a particularly fat-rich diet (Pesquero et al., Biol. Chem. 2006, 387, 119-126). B1R antagonists are therefore also suitable for treating obesity.

B1R antagonists are in particular suitable for treating pain, in particular inflammatory pain and neuropathic pain (Calixto et al. Br. J. Pharmacol 2004, 1-16), in this connection in particular diabetic neuropathy (Gabra et al., Biol. Chem. 2006, 387, 127-143). Furthermore they are suitable for the treatment of migraine.

In the development of B1R modulators there is the problem however that the human and rat B1R receptors differ so greatly that many compounds that are good B1R modulators on the human receptor have only a poor affinity or no affinity at all for the rat receptor. This significantly complicates animal pharmacological investigations since many investigations are normally carried out on rats. If however a compound has no effect on the rat receptor, then neither the action nor side effects on rats can be investigated. This has already led to the creation of transgenic animals with human B1 receptors for animal pharmacological investigations (Hess et al., Biol. Chem. 2006; 387(2): 195-201). Working with transgenic animals is however more costly than working with unaltered animals. Since long-term toxicity investigations on rats are in particular part of the routine investigations in drug research and development however, these are not practicable if the compound is ineffective on the receptor, and an important established tool for checking safety is therefore lacking in the development of such compounds. There is therefore a need for new B1R modulators, in which connection B1R modulators that bind to the rat receptor as well as to the human receptor offer particular advantages.

SUMMARY OF THE INVENTION

An object of the present invention was accordingly to provide new compounds that are suitable in particular as pharmacological active constituents in medicaments, preferably in medicaments for treating disorders or diseases that are at least partially mediated by B1R receptors.

This object has been achieved by the substituted sulfonamide compounds according to the invention as described and claimed hereinafter.

The present invention provides substituted sulfonamide compounds corresponding to formula I:

wherein

-   m and n each independently denote 0, 1 or 2; -   p denotes 1 or 2; -   Q denotes —O— or —CH₂—; -   X denotes N or CR⁵; -   Y denotes N or CR⁶; -   Z denotes N or CR⁷; -   R¹ denotes aryl, heteroaryl, or an aryl or heteroaryl group bonded     via a C₁₋₆-alkylene group; -   R² denotes H, C₁₋₆-alkyl, aryl, heteroaryl, or an aryl or heteroaryl     group bonded via a C₁₋₆-alkylene group, C₂₋₆-alkenylene group or     C₂₋₆-alkynylene group; -   R³ denotes H, C₁₋₆-alkyl, aryl, heteroaryl, or an aryl or heteroaryl     group bonded via a C₁₋₆-alkylene group, C₂₋₆-alkenylene group or     C₂₋₆-alkynylene group; -   R⁴ denotes H, halogen, CN, NO₂, C₁₋₆-alkyl, aryl, heteroaryl, or an     aryl or heteroaryl group bonded via a C₁₋₆-alkylene group,     C₂₋₆-alkenylene group or C₂₋₆-alkynylene group; -   R⁵, R⁶ and R⁷ each independently denote H, halogen, CN, C₁₋₆-alkyl,     —NH(C₁₋₆-alkyl), —N(C₁₋₆-alkyl)₂, —C₁₋₆-alkylene-NH(C₁₋₆-alkyl),     —C₁₋₆-alkylene-N(C₁₋₆-alkyl)₂, C₃₋₈-cycloalkyl, heterocyclyl, aryl,     heteroaryl, or a C₃₋₈-cycloalkyl, heterocyclyl, aryl or heteroaryl     group bonded via a C₁₋₆-alkylene group, C₂₋₆-alkenylene group or     C₂₋₆-alkynylene group;     wherein     -   said C₁₋₆-alkyl, C₁₋₆-alkylene, C₂₋₆-alkenylene,         C₂₋₆-alkynylene, C₃₋₈-cycloalkyl, heterocyclyl, aryl and         heteroaryl groups may be unsubstituted or mono- or         poly-substituted with identical or different substituents, and     -   said C₁₋₆-alkyl, C₁₋₆-alkylene, C₂₋₆-alkenylene, and         C₂₋₆-alkynylene groups may be branched or unbranched;         in the form of an individual enantiomer or an individual         diastereomer, in the form of the racemate, enantiomers,         diastereomers, mixtures of the enantiomers and/or diastereomers,         as well as in each case in the form of their bases and/or         physiologically compatible salts.

In the context of the present invention the term “halogen” preferably denotes the groups F, Cl, Br and I, and particularly preferably the denotes groups F, Cl and Br.

In the context of the present invention, the expression “C₁₋₆-alkyl” includes acyclic saturated hydrocarbon groups with 1, 2, 3, 4, 5 or 6 carbon atoms, which may be branched or straight-chain (unbranched) as well as unsubstituted or monosubstituted or polysubstituted, for example 2, 3, 4 or 5 times, with identical or different substituents. Preferred alkyl groups are selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl and hexyl. Particularly preferred alkyl groups are selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl and tert-butyl.

In the context of the present invention the expression “C₃₋₈-cycloalkyl” denotes cyclic saturated hydrocarbons with 3, 4, 5, 6, 7 or 8 carbon atoms, which may be unsubstituted or monosubstituted or polysubstituted on one or more ring members, for example with 2, 3, 4 or 5 identical or different substituents. Preferred C₃₋₈-cycloalkyl groups are selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

In the context of the present invention, the expression “heterocyclyl” denotes monocyclic or polycyclic, in particular mono-, bi- or tricyclic organic groups, in which at least one cycle contains 1 heteroatom or 2, 3, 4 or 5 identical or different heteroatoms, which is/are preferably selected from the group consisting of N, O and S. Each heterocyclyl group can be unsubstituted or monosubstituted or polysubstituted on one or more ring members, for example with 2, 3, 4 or 5 identical or different substituents. Saturated or unsaturated heterocyclyl are understood in particular to denote monocyclic 5-membered or 6-membered groups with at least one heteroatom selected from the group consisting of N, O and S, wherein a further 5-membered or 6-membered, saturated, unsaturated or aromatic cycle, which likewise can contain at least one heteroatom selected from the group consisting of N, O and S, can be condensed onto these groups. Examples are the benzo-condensed or pyridino-condensed analogues of the aforementioned monocyclic 5- or 6-membered compounds. Preferably a saturated or unsaturated heterocyclyl group can be selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrazolinyl, morpholinyl, tetrahydropyranyl, dioxanyl, dioxolanyl, indolinyl, isoindolinyl and

Unless otherwise specified, the substitution with a heterocyclyl group can take place at any suitable position of the heterocyclyl group.

In the context of the present invention, the term “aryl” denotes aromatic hydrocarbons, in particular phenyl and naphthyl groups. The aryl groups can also be condensed with further saturated, (partially) unsaturated or aromatic ring systems. Each aryl group can be unsubstituted or monosubstituted or polysubstituted, for example 2, 3, 4 or 5 times, in which the aryl substituents can be identical or different and can be in any arbitrary and possible position of the aryl. Preferably aryl can be selected from the group consisting of phenyl, 1-naphthyl and 2-naphthyl, which can in each case be unsubstituted or monosubstituted or polysubstituted, for example with 2, 3, 4 or 5 groups.

In the context of the present invention, the term “heteroaryl” denotes a 5-, 6- or 7-membered cyclic aromatic group, which contains at least 1, possibly also 2, 3, 4 or 5 heteroatoms, in which the heteroatoms can be identical or different and the heteroaryl can be unsubstituted or monosubstituted or polysubstituted, for example 2, 3, 4 or 5 times, with identical or different substituents. The substituents can be bonded in any arbitrary and possible position of the heteroaryl. The heterocycle can also be part of a bicyclic or polycyclic, in particular of a monocyclic, bicyclic or tricyclic system, which can then overall contain more than 7 members, preferably up to 14 members. Preferred heteroatoms are selected from the group consisting of N, O and S. The heteroaryl group can preferably be selected from the group consisting of pyrrolyl, indolyl, furyl, (furanyl), benzofuranyl, thienyl (thiophenyl), benzothienyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, benzodioxolanyl, benzodioxanyl, benzooxazolyl, benzooxadiazolyl, imidazothiazolyl, dibenzofuranyl, dibenzothienyl, phthalazinyl, pyrazolyl, imidazolyl, thiazolyl, oxadiazolyl, isoxazoyl, pyridinyl (pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, indazolyl, purinyl, indolizinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenazinyl, phenothiazinyl and oxadiazolyl, wherein the bonding to the general structure I can take place via any arbitrary and possible ring member of the heteroaryl group. Particularly preferably the heteroaryl group can be selected from the group consisting of furyl, thienyl and pyridinyl.

In the context of the present invention, the expression “C₁₋₆-alkylene group” includes acyclic saturated hydrocarbon groups with 1, 2, 3, 4, 5 or 6 C atoms, which can be branched or straight-chain (unbranched) as well as unsubstituted or monosubstituted or polysubstituted, for example 2, 3, 4 or 5 times, with identical or different substituents, and which couple a corresponding group to the overall general structure. Preferably the alkylene groups can be selected from the group consisting of —CH₂—, —CH₂—CH₂—, —CH(CH₃)—, —CH₂—CH₂—CH₂—, —CH(CH₃)—CH₂—, —CH(CH₂CH₃)—, —CH₂—(CH₂)₂—CH₂—, —CH(CH₃)—CH₂—CH₂—, —CH₂—CH(CH₃)—CH₂—, —CH(CH₃)—CH(CH₃), —CH(CH₂CH₃)—CH₂—, —C(CH₃)₂—CH₂, —CH(CH₂CH₂CH₃)—, —C(CH₃)(CH₂CH₃)—, —CH₂—(CH₂)₃—CH₂—, —CH(CH₃)—CH₂—CH₂—CH₂—, —CH₂—CH(CH₃)—CH₂—CH₂—, —CH(CH₃)—CH₂—CH(CH₃)—, —CH(CH₃)CH(CH₃)—CH₂—, —C(CH₃)₂—CH₂—CH₂—, —CH₂—C(CH₃)₂—CH₂—, —CH(CH₂CH₃)—CH₂—CH₂—, —CH₂—CH(CH₂CH₃)—CH₂—, —C(CH₃)₂—CH(CH₃)—, —CH(CH₂CH₃)—CH(CH₃)—, —C(CH₃)(CH₂CH₃)—CH₂—, —CH(CH₂CH₂CH₃)—CH₂—, —C(CH₂CH₂CH₃)—CH₂—, —CH(CH₂CH₂CH₂CH₃)—, —C(CH₃)(CH₂CH₂CH₃)—, —C(CH₂CH₃)₂— and —CH₂—(CH₂)₄—CH₂—. Particularly preferably the alkylene groups can be selected from the group consisting of —CH₂—, —CH₂—CH₂— and —CH₂—CH₂—CH₂—.

In the context of the present invention, the expression “C₂₋₆-alkenylene group” includes acyclic, monosubstituted or polysubstituted, for example 2, 3 or 4 times, unsaturated hydrocarbon groups with 2, 3, 4, 5 or 6 carbon atoms, which may be branched or straight-chain (unbranched) as well as unsubstituted or monosubstituted or polysubstituted, for example 2, 3, 4 or 5 times, with identical or different substituents, and which couple a corresponding group to the overall general structure. In this connection the alkenylene groups contain at least one C═C double bond. Preferably the alkenylene groups can be selected from the group consisting of —CH═CH—, —CH═CH—CH₂—, —C(CH₃)═CH₂—, —CH═CH—CH₂—CH₂—, —CH₂—CH═CH—CH₂—, —CH═CH—CH═CH—, —C(CH₃)═CH—CH₂—, —CH═C(CH₃)—CH₂—, —C(CH₃)═C(CH₃)—, —C(CH₂CH₃)═CH—, —CH═CH—CH₂—CH₂—CH₂—, —CH₂CH═CH₂—CH₂—CH₂—, —CH═CH═CH—CH₂—CH₂— and —CH═CH₂—CH—CH═CH₂—.

In the context of the present invention, the expression “C₂₋₆-alkynylene group” includes acyclic, monosubstituted or polysubstituted, for example 2, 3 or 4 times, unsaturated hydrocarbon groups with 2, 3, 4, 5 or 6 C atoms, which may be branched or straight-chain (unbranched) as well as unsubstituted or monosubstituted or polysubstituted, for example 2, 3, 4 or 5 times, with identical or different substituents, and which couple a corresponding group to the overall general structure. In this connection the alkynylene groups contain at least one C≡C triple bond. Preferably the alkynylene groups can be selected from the group consisting of —C≡C—, —C≡C—CH₂—, —C≡C—CH₂—CH₂—, —C≡C—CH(CH₃)—, —CH₂—C≡C—CH₂—, —C≡C—C≡C—, —C≡C—C(CH₃)₂—, —C≡C—CH₂—CH₂CH₂—, —CH₂—C≡C—CH₂—CH₂—, —C≡C—C≡C—CH₂— and —C≡C—CH₂—C≡C—.

In the context of the present invention, the expression “aryl or heteroaryl group bonded via a C₁₋₆-alkylene group, C₂₋₆-alkenylene group or C₂₋₆-alkynylene group” denotes that the C₁₋₆-alkylene groups, C₂₋₆-alkenylene groups or C₂₋₆-alkynylene groups as well as aryl and/or heteroaryl have the meanings given above and the aryl and/or heteroaryl is/are bonded via a C₁₋₆-alkylene group, C₂₋₆-alkenylene group or C₂₋₆-alkynylene group to the overall general structure. Examples of such groups include benzyl, phenethyl and phenylpropyl groups.

In the context of the present invention, the expression “C₃₋₈-cycloalkyl and heterocyclyl bonded via a C₁₋₆-alkylene group, C₂₋₆-alkenylene group or C₂₋₆-alkynylene group” denotes that the C₁₋₆-alkylene group, C₂₋₆-alkenylene group, C₂₋₆-alkynylene group, C₃₋₈-cycloalkyl and heterocyclyl have the meanings given above and C₃₋₈-cycloalkyl and heterocyclyl are bonded via a C₁₋₆-alkylene group, C₂₋₆-alkenylene group or C₂₋₆-alkynylene group to the overall general structure.

In the context of the present invention, the term “substituted” used in connection with “alkyl”, “alkylene”, “alkenylene”, “alkynylene” and “cycloalkyl” is understood to denote the replacement of a hydrogen atom by F, Cl, Br, I, CN, NH₂, NH—C₁₋₆-alkyl, NH—C₁₋₆-alkylene-OH, C₁₋₆-alkyl, N(C₁₋₆-alkyl)₂, N(C₁₋₆-alkylene-OH)₂, NO₂, SH, S—C₁₋₆-alkyl, S-benzyl, O—C₁₋₆-alkyl, OH, O—C₁₋₆-alkylene-OH, ═O, O-benzyl, C(═O)C₁₋₆-alkyl, CO₂H, CO₂—C₁₋₆-alkyl, or benzyl, wherein polysubstituted groups are understood to be those groups that are substituted several times, for example twice or three times, either on different or on the same atoms, for example three times on the same carbon atom as in the case of CF₃ or CH₂CF₃, or at different sites as in the case of CH(Cl)—CH═CH—CHCl₂. The polysubstitution can be carried out with identical or different substituents, as for example in the case of CH(OH)—CH═CH—CHCl₂.

In connection with “heterocyclyl” the term “substituted” is understood to denote the replacement of a hydrogen atom on one or more ring members by F, Cl, Br, I, —CN, NH₂, NH—C₁₋₆-alkyl, NH—C₁₋₆-alkylene-OH, C₁₋₆-alkyl, N(C₁₋₆-alkyl)₂, N(C₁₋₆-alkylene-OH)₂, pyrrolinyl, piperazinyl, morpholinyl, NO₂, SH, S—C₁₋₆-alkyl, S-benzyl, O—C₁₋₆-alkyl, OH, O—C₁₋₆-alkylene-OH, ═O, O-benzyl, C(═O)C₁₋₆-alkyl, CO₂H, CO₂—C₁₋₆-alkyl or benzyl. The polysubstitution can be carried out with identical or different substituents. In particular the hydrogen bonded to a N-heteroatom can be substituted by a C₁₋₆-alkyl group.

With regard to “aryl” and “heteroaryl”, in the context of the present invention, the term “substituted” is understood to denote monosubstitution or polysubstitution, for example 2, 3, 4 or 5 times, of one or more hydrogen atoms of the corresponding ring system by F, Cl, Br, I, CN, NH₂, NH—C₁₋₆-alkyl, NH—C₁₋₆-alkylene-OH, N(C₁₋₆-alkyl)₂, N(C₁₋₆-alkylene-OH)₂, NH-aryl¹, N(aryl¹)₂, N(C₁₋₆-alkyl)aryl¹, pyrrolinyl, piperazinyl, morpholinyl, NO₂, SH, S—C₁₋₆-alkyl, OH, O—C₁₋₆-alkyl, O—C₁₋₆-alkyl-OH, C(═O)C₁₋₆-alkyl, NHSO₂C₁₋₆-alkyl, NHCOC₁₋₆-alkyl, CO₂H, CH₂SO₂-phenyl, CO₂—C₁₋₆-alkyl, OCF₃, CF₃, —O—CH₂—O—, —O—CH₂—CH₂—O—, —O—C(CH₃)₂—CH₂—, unsubstituted C₁₋₆-alkyl, pyrrolidinyl, imidazolyl, piperidinyl, benzyloxy, phenoxy, phenyl, naphthyl, pyridinyl, —C₁₋₃-alkylene-aryl¹, benzyl, thienyl, furyl, wherein aryl¹ denotes phenyl, furyl, thienyl or pyridinyl, on one or various atoms, wherein the aforementioned substituents—unless otherwise specified—may optionally for their part be substituted by the aforementioned substituents. The polysubstitution of aryl and heteroaryl can take place with identical or different substituents. Preferred substituents for aryl and heteroaryl can be selected from the group consisting of —O—C₁₋₃-alkyl, C₁₋₆-alkyl, F, Cl, Br, I, CF₃, OCF₃, OH, SH, phenyl, naphthyl, furyl, thienyl and pyridinyl, in particular from the group consisting of F, Cl, Br, CF₃, CH₃ and OCH₃.

In the context of the present invention the symbol

used in the formulas denotes a coupling of a corresponding group to the respective overall general structure.

In the context of the present invention, the expression “physiologically compatible salt” is to be understood to denote salts of the compounds according to the invention with inorganic or organic acids that are physiologically compatible, especially when used in humans and/or mammals. Examples of suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, maleic acid, lactic acid, citric acid, glutamic acid, 1,1-dioxo-1,2-dihydroλ⁶-benzo[d]isothiazol-3-one (saccharinic acid), monomethylsebacic acid, 5-oxoproline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, α-lipoic acid, acetylglycine, hippuric acid, phosphoric acid and/or aspartic acid. Particularly preferred are the salts of hydrochloric acid (hydrochlorides) as well as of citric acid (citrates).

In one preferred embodiment of the present invention, the group R¹ in the substituted sulfonamide compounds according to the invention denotes phenyl, naphthyl, indolyl, benzofuranyl, benzothiophenyl (benzothienyl); benzooxazolyl, benzooxadiazolyl, pyrrolyl, furanyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazothiazolyl, carbazolyl, dibenzofuranyl or dibenzothiophenyl (dibenzothienyl), preferably denotes phenyl, naphthyl, benzothiophenyl, benzooxadiazolyl, thiophenyl, pyridinyl, imidazothiazolyl or dibenzofuranyl, and particularly preferably denotes phenyl or naphthyl, in each case unsubstituted or monosubstituted or polysubstituted with identical or different substituents, wherein the substituents are preferably selected from the group consisting of —O—C₁₋₃-alkyl, C₁₋₆-alkyl, F, Cl, Br, I CF₃, OCF₃, OH, SH, phenyl, naphthyl, furyl, thienyl and pyridinyl.

In another preferred embodiment of the present invention, the group R¹ in the substituted sulfonamide compounds according to the invention denotes phenyl or naphthyl, wherein the phenyl or naphthyl may be unsubstituted or monosubstituted or polysubstituted, for example 2, 3, 4 or 5 times, with identical or different substituents selected from the group consisting of methyl, methoxy, CF₃, OCF₃, F, Cl and Br.

In still another preferred embodiment, the group R¹ in the sulfonamide compounds according to the invention is selected from the group consisting of 4-methoxy-2,3,6-trimethylphenyl, 4-methoxy-2,6-dimethylphenyl, 4-methoxy2,3,5-trimethylphenyl, 2,4,6-trimethylphenyl, 2-chloro-6-methylphenyl, 2,4,6-trichlorophenyl, 2-chloro-6-(trifluoromethyl)phenyl, 2,6-dichloro-4-methoxyphenyl, 2-methylnaphthyl, 2-chloronaphthyl, 2-fluoronaphthyl, 2-chloro-4-(trifluoromethoxy)phenyl, 4-chloro-2,5-dimethylphenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 2(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 1-naphthyl and 2-naphthyl.

In yet another preferred embodiment the group R¹ in the sulfonamide compounds according to the invention is selected from the group consisting of 4-methoxy-2,3,6-trimethylphenyl, 4-methoxy-2,6-dimethylphenyl, 4-methoxy2,3,5-trimethylphenyl, 2,4,6-trimethylphenyl, 4-chloro-2,5-dimethylphenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 2-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 1-naphthyl and 2-naphthyl.

In another preferred embodiment, the group R¹ in the sulfonamide compounds according to the invention is selected from the group consisting of 4-methoxy-2,3,6-trimethylphenyl, 4-methoxy-2,6-dimethylphenyl, 4-methoxy-2,3,5-trimethylphenyl, 2,4,6-trimethylphenyl, 1-naphthyl and 2-naphthyl.

Preferably R² in the sulfonamide compounds according to the invention denotes H, C₁₋₆-alkyl or aryl; or denotes an aryl bonded via a C₁₋₆-alkylene group, C₂₋₆-alkenylene group or C₂₋₆-alkynylene group, wherein the aryl may be unsubstituted or monosubstituted or polysubstituted with identical or different substituents selected from the group consisting of C₁₋₆-alkyl, C₁₋₆-alkyl-O—, F, Cl, Br, I CF₃, OCF₃, OH and SH.

In a further preferred embodiment of the sulfonamide compounds according to the invention, R² denotes H, C₁₋₆-alkyl or phenyl; or denotes a phenyl bonded via a C₁₋₆-alkylene group, wherein the phenyl may be unsubstituted or monosubstituted or polysubstituted with identical or different substituents selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, methoxy, F, Cl, Br, I, CF₃, OCF₃ and OH.

In a further preferred embodiment of the sulfonamide compounds according to the invention, R² denotes H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, benzyl or phenethyl.

Preferably R³ in the sulfonamide compounds according to the invention can denote H, C₁₋₆-alkyl or aryl; or can denote an aryl bonded via a C₁₋₆-alkylene group, C₂₋₆-alkenylene group or C₂₋₆-alkynylene group, the aryl in each case being unsubstituted or monosubstituted or polysubstituted with identical or different substituents selected from the group consisting of C₁₋₆-alkyl, C₁₋₆-alkyl-O—, F, Cl, Br, I, CF₃, OCF₃, OH and SH.

In a further preferred embodiment of the sulfonamide compounds according to the invention, R³ denotes H or phenyl, wherein the phenyl may be unsubstituted or monosubstituted or polysubstituted with identical or different substituents selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, methoxy, F, Cl, Br, I, CF₃, OCF₃ and OH.

In another preferred embodiment of the sulfonamide compounds according to the invention, R³ denotes H or unsubstituted phenyl.

In yet another preferred embodiment of the sulfonamide compounds according to the invention:

-   -   if Q=—O—, then m and n are each equal to 1, and     -   if Q=—CH₂—, then the sum of m+n=0 or 1.

In a further preferred embodiment of the sulfonamide compounds according to the invention:

-   -   if Q=—O—, then m and n each equal 1, and     -   if Q=—CH₂—, then the sum of m+n=0.

In still another preferred embodiment of the substituted sulfonamide compounds according to the invention, p denotes 1.

In a further preferred embodiment of the sulfonamide compounds according to the invention, R⁴ denotes H, C₁₋₆-alkyl, aryl, heteroaryl, or an aryl or heteroaryl group bonded via a C₁₋₆-alkylene group, C₂₋₆-alkenylene group or C₂₋₆-alkynylene group, wherein the aryl or heteroaryl preferably is selected from the group consisting of phenyl, naphthyl, pyridinyl, thienyl and furyl, and wherein the aryl or heteroaryl may be unsubstituted or monosubstituted or polysubstituted by identical or different substituents selected from the group consisting of O—C₁₋₃-alkyl, unsubstituted C₁₋₆-alkyl, F, Cl, Br, I, CF₃, OCF₃, OH and SH.

In a further preferred embodiment of the sulfonamide compounds according to the invention R⁴ denotes H, C₁₋₆-alkyl, phenyl, furyl, thienyl, pyridinyl, or a phenyl, furyl, thienyl or pyridinyl group bonded via a C₁₋₃-alkylene group, wherein the phenyl, furyl, thienyl or pyridinyl may be unsubstituted or monosubstituted or polysubstituted by identical or different substituents selected from the group consisting of —O—C₁₋₃-alkyl, unsubstituted C₁₋₆-alkyl, F, Cl, Br, I, CF₃, OCF₃, OH, SH.

In yet another preferred embodiment of the sulfonamide compounds according to the invention, R⁴ denotes a group selected from the group consisting of H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, phenyl, 2,3-dimethylphenyl, 3,4-dimethylphenyl, 2-tert-butylphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 3,4-difluorophenyl, 2(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 2-fluoro-4(trifluoromethyl)phenyl, 3-fluoro-4-(trifluoromethyl)phenyl, benzyl, phenethyl, thienyl, pyridyl and 6-chloro-pyridin-3-yl.

In still another preferred embodiment of the present invention, X in the substituted sulfonamide compounds according to the invention denotes N; Y denotes CR⁶, and Z denotes CR⁷.

In a further embodiment of the present invention, in the substituted sulfonamide compounds according to the invention X denotes N, Y denotes N, and Z denotes CR⁷.

In a further embodiment of the present invention, in the substituted sulfonamide compounds according to the invention X denotes CR⁵, Y denotes CR⁶ and Z denotes CR⁷.

In a still further preferred embodiment of the sulfonamide compounds according to the invention, R⁵, R⁶ and R⁷ each independently denote H, halogen, C₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂, —C₁₋₆-alkylene-N(C₁₋₆-Alkyl)₂, a 5-, 6- or 7-membered heterocyclyl, 5- or 6-membered heteroaryl, a 5- or 6-membered heteroaryl, or a 5-, 6- or 7-membered heterocyclyl bonded via a C₁₋₆-alkylene group, wherein heterocyclyl comprises one or two identical or different heteroatoms selected from the group consisting of N and O, and may be unsubstituted or monosubstituted or identically or differently polysubstituted with C₁₋₆-alkyl.

In a further preferred embodiment of the sulfonamide compounds according to the invention, R⁵, R⁶ and R⁷ each independently denote H, F, Cl, Br, I, C₁₋₆-alkyl, or a group selected from the group consisting of:

-   -   wherein     -   R⁸ and R⁹ each independently denote a C₁₋₆-alkyl group;     -   j is 1, 2 or 3;     -   R¹⁰ denotes a group selected from the group consisting of H,         methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,         sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl and         cyclohexyl; and     -   M¹, M² und M³ each independently denote N or CH, wherein one of         M¹, M² and M³ represents N, and the other two of M¹, M² and M³         each represent CH.

Preferably R⁵ in the compounds according to the invention denotes H.

In a further preferred embodiment of the compounds according to the invention R⁶ denotes H or a group selected from the group consisting of

-   -   wherein     -   R⁸ and R⁹ each independently denote a C₁₋₆-alkyl group;     -   j is 1, 2 or 3; and     -   M¹, M² und M³ each independently denote N or CH, wherein one of         M¹, M² and M³ represents N, and the other two of M¹, M² and M³         each represent CH.

In another preferred embodiment of the compounds according to the invention, R⁷ denotes H, F, Cl, Br, I, C₁₋₆-alkyl, or a group selected from the group consisting of:

-   -   wherein     -   R⁸ and R⁹ each independently denote a C₁₋₆-alkyl group,     -   j is 1, 2 or 3; and     -   M¹, M² and M³ each independently denote N or CH, wherein one of         M¹, M² and M³ represents N, and the other two of M¹, M² and M³         each represent CH.

Also preferred are substituted sulfonamide compounds of the invention wherein:

-   m and n each independently denote 0 or 1; -   p is 1; -   Q denotes —O— or —CH₂; -   X denotes N or CR⁵; -   Y denotes N or CR⁶; -   Z denotes N or CR⁷; -   R¹ denotes phenyl, naphthyl, indolyl, benzofuranyl,     benzothiophenyl(benzothienyl); benzooxazolyl, benzooxadiazolyl,     pyrrolyl, furanyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl,     pyrazinyl, imidazothiazolyl, carbazolyl, dibenzofuranyl or     dibenzothiophenyl(dibenzothienyl), preferably phenyl, naphthyl,     benzothiophenyl, benzooxadiazolyl, thiophenyl, pyridinyl,     imidazothiazolyl or dibenzofuranyl, and particularly preferably     denotes phenyl or naphthyl, in each case unsubstituted or     monosubstituted or polysubstituted with identical or different     substituents, wherein the substituents are preferably selected from     the group consisting of —O—C₁₋₃-alkyl, C₁₋₆-alkyl, F, Cl, Br, I CF₃,     OCF₃, OH, SH, phenyl, naphthyl, furyl, thienyl and pyridinyl; -   R² denotes H, C₁₋₆-alkyl, aryl, or an aryl group bonded via a     C₁₋₆-alkylene group, C₂₋₆-alkenylene group or C₂₋₆-alkynylene group,     wherein the aryl may be unsubstituted or monosubstituted or     polysubstituted with identical or different substituents selected     from the group consisting of C₁₋₆-alkyl, C₁₋₆-alkyl-O—, F, Cl, Br,     I, CF₃, OCF₃, OH, and SH; -   R³ denotes H, C₁₋₆-alkyl, aryl, or an aryl group bonded via a     C₁₋₆-alkylene group, C₂₋₆-alkenylene group or C₂₋₆-alkynylene group,     which aryl may be unsubstituted or monosubstituted or     polysubstituted with identical or different substituents selected     from the group consisting of C₁₋₆-alkyl, C₁₋₆-alkyl-O—, F, Cl, Br,     I, CF₃, OCF₃, OH and SH; -   R⁴ denotes H, C₁₋₆-alkyl, aryl, heteroaryl, or an aryl or heteroaryl     group bonded via a C₁₋₆-alkylene group, C₂₋₆-alkenylene group or     C₂₋₆-alkynylene group, wherein the aryl or heteroaryl is preferably     selected from the group consisting of phenyl, naphthyl, pyridinyl,     thienyl and furyl, and may be unsubstituted or monosubstituted or     polysubstituted with identical or different substituents selected     from the group consisting of O—C₁₋₃-alkyl, unsubstituted C₁₋₆-alkyl,     F, Cl, Br, I, CF₃, OCF₃, OH and SH. -   R⁵, R⁶ and R⁷ each independently denote H, halogen, C₁₋₆-alkyl,     —N(C₁₋₆-alkyl)₂, —C₁₋₆-alkylene-N(C₁₋₆-alkyl)₂, 5- or 6-membered     heterocyclyl, 5- or 6-membered heteroaryl, or a 5- or 6-membered     heteroaryl or 5- or 6-membered heterocyclyl group bonded via a     C₁₋₆-alkylene group, wherein heterocyclyl comprises 1 or 2 identical     or different heteroatoms selected from the group consisting of N and     O and may be unsubstituted or is monosubstituted or identically or     differently polysubstituted with C₁₋₆-alkyl;     in the form of an individual enantiomer or an individual     diastereomer, in the form of the racemate, enantiomers,     diastereomers, mixtures of the enantiomers and/or diastereomers, as     well as in the form of their bases and/or physiologically compatible     salts.

In addition substituted sulfonamide compounds according to the invention are preferred in which

-   if Q=—O—, then m and j are each 1, and -   if Q=—CH₂—, then the sum of m+n=0 or 1; -   p is 1; -   R¹ denotes phenyl or naphthyl, which may be unsubstituted or     monosubstituted or identically or differently polysubstituted with     substituents selected from the group consisting of methyl, methoxy,     CF₃, F, Cl and Br; -   R² denotes H, C₁₋₆-alkyl, phenyl, or a phenyl group bonded via a     C₁₋₆-alkylene group, wherein the phenyl may be unsubstituted or     monosubstituted or polysubstituted with identical or different     substituents selected from the group consisting of methyl, ethyl,     n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,     methoxy, F, Cl, Br, I, CF₃, OCF₃ and OH; -   R³ denotes H or phenyl, which phenyl may be unsubstituted or     monosubstituted or polysubstituted with identical or different     substituents selected from the group consisting of methyl, ethyl,     n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,     methoxy, F, Cl, Br, I, CF₃, OCF₃ and OH; -   R⁴ denotes H, C₁₋₆-alkyl, phenyl, furyl, thienyl or pyridinyl; or     denotes a phenyl, furyl, thienyl or pyridinyl bonded via a     C₁₋₃-alkylene group, wherein the phenyl, furyl, thienyl or pyridinyl     are in each case unsubstituted or monosubstituted or identically or     differently polysubstituted, the substituents being selected from     the group consisting of —O—C₁₋₃-alkyl, unsubstituted C₁₋₆-alkyl, F,     Cl, Br, I, CF₃, OCF₃, OH, SH; -   R⁵ denotes H; -   R⁶ denotes H or a group selected from the group consisting of:

-   -   wherein     -   R⁸ and R⁹ each independently denote a C₁₋₆-alkyl group;     -   j is 1, 2 or 3; and     -   M¹, M² und M³ each independently denote N or CH, wherein one of         M¹, M² and M³ represents N, and the other two of M¹, M² and M³         each represent CH;

-   R⁷ denotes H, F, Cl, Br, I, C₁₋₆-alkyl, or a group selected from the     group consisting of

-   -   wherein     -   R⁸ and R⁹ each independently denote a C₁₋₆-alkyl group;     -   j is 1, 2 or 3; and     -   M¹, M² und M³ each independently denote N or CH, wherein one of         M¹, M² and M³ represents N, and the other two of M¹, M² and M³         each represent CH.

According to a further embodiment of the present invention substituted sulfonamide compounds are preferred in which

-   m=1, n=1, and Q denotes —O—; or -   m=1, n=0, and Q denotes —CH₂—; or -   m=0, n=1, and Q denotes —CH₂—; or -   m=0, n=0 and Q denotes —CH₂—; -   p denotes 1; -   X denotes N or CR⁵; -   Y denotes N or CR⁶; -   Z denotes N or CR⁷; -   R¹ denotes phenyl or naphthyl, which may be unsubstituted or     monosubstituted or identically or differently disubstituted,     trisubstituted, quadruply substituted or pentasubstituted with     substituents selected from the group consisting of methyl, methoxy,     CF₃, F, Cl and Br; -   R² denotes H, methyl, ethyl, n-propyl, iso-propyl, n-butyl,     iso-butyl, sec-butyl, tert-butyl, phenyl, or a phenyl group bonded     via a —CH₂—, —(CH₂)₂— or —(CH₂)₃— group, wherein the phenyl may be     unsubstituted or monosubstituted or disubstituted, trisubstituted,     tetrasubstituted or pentasubstituted with identical or different     substituents selected from the group consisting of methyl, ethyl,     n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,     methoxy, F, Cl, Br, I, CF₃, OCF₃ and OH; -   R³ denotes H or unsubstituted phenyl, -   R⁴ denotes H, methyl, ethyl, n-propyl, iso-propyl, n-butyl,     iso-butyl, sec-butyl, tert-butyl, phenyl, furyl, thienyl, pyridinyl,     or a phenyl, furyl, thienyl or pyridinyl group bonded via a —(CH₂)—,     —(CH₂)₂— or —(CH₂)₃— group, wherein the phenyl, furyl, thienyl or     pyridinyl may be unsubstituted or monosubstituted, disubstituted or     trisubstituted with substituents independently selected from the     group consisting of methoxy, ethoxy, n-propoxy, iso-propoxy, methyl,     ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl,     tert-butyl, F, Cl, Br, I, CF₃, OCF₃, OH and SH; -   R⁵ denotes H; -   R⁶ denotes H or a group selected from the group consisting of

-   -   wherein     -   R⁸ and R⁹ each denote a methyl group;     -   j is 1, 2 or 3; and     -   M¹, M² und M³ each independently denote N or CH, wherein one of         M¹, M² and M³ represents N, and the other two of M¹, M² and M³         each represent CH;

-   R⁷ denotes H, F, Cl, Br, I, methyl, ethyl, n-propyl, iso-propyl,     n-butyl, iso-butyl, sec-butyl, tert-butyl, or a group selected from     the group consisting of

wherein

-   -   R⁸ and R⁹ each denote a methyl group;     -   j is 1, 2 or 3; and     -   M¹, M² und M³ each independently denote N or CH, wherein one of         M¹, M² and M³ represents N, and the other two of M¹, M² and M³         each represent CH.

Also preferred are sulfonamide compounds according to the invention corresponding to formula Ib

wherein

-   X denotes N or CR⁵; -   Y denotes N or CR⁶; -   Z denotes N or CR⁷; -   R⁴ denotes H, methyl, ethyl, n-propyl, iso-propyl, n-butyl,     iso-butyl, sec-butyl, tert-butyl, phenyl, furyl, thienyl, pyridinyl,     or a phenyl group bonded via a —(CH₂)—, —(CH₂)₂— or —(CH₂)₃— group,     wherein the phenyl, furyl, thienyl or pyridinyl may be unsubstituted     or monosubstituted or identically or differently disubstituted or     trisubstituted with substituents independently selected from the     group consisting of methoxy, ethoxy, n-propoxy, iso-propoxy, methyl,     ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, F, Cl,     Br, I CF₃, OCF₃, OH and SH; -   R⁵ denotes H; -   R⁶ denotes H or a group selected from the group consisting of

-   -   wherein     -   R⁸ and R⁹ each independently denote a methyl group;     -   j is 1, 2 or 3; and     -   M¹, M² und M³ each independently denote N or CH, wherein one of         M¹, M² and M³ represents Nn and the other two of M¹, M² and M³         each represent CH;

-   R⁷ denotes H, F, Cl, Br, I, methyl, ethyl, n-propyl, iso-propyl,     n-butyl, iso-butyl, sec-butyl, tert-butyl, or a group selected from     the group consisting of:

-   -   wherein     -   R⁸ and R⁹ each independently denote a methyl group;     -   j is 1, 2 or 3; and     -   M¹, M² und M³ each independently denote N or CH, wherein one of         M¹, M² and M³ represents N, and the other two of M¹, M² and M³         each represent CH.

According to a further preferred embodiment of the invention, the sulfonamide compounds according to the invention are selected from the group consisting of:

-   (1)     N-(2-(2-(6-((dimethylamino)methyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzene-sulfonamide, -   (2)     4-methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(2-(piperidin-1-ylmethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (3)     N-(2-(2-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide, -   (4)     (R)-N-(3-oxo-1-phenyl-3-(2-(piperidin-1-ylmethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)propyl)naphthalene-2-sulfonamide, -   (5)     (R)-N-(3-(3-chloro-2-(piperidin-1-ylmethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-3-oxo-1-phenylpropyl)naphthalene-2-sulfonamide, -   (6)     N-(2-(2-(3-chloro-2-(piperidin-1-ylmethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide, -   (7)     4-methoxy-N,2,6-trimethyl-N-(2-(2-(6-(morpholinomethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide, -   (8)     N-(3-oxo-1-phenyl-3-(6-(pyrrolidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)propyl)naphthalene-2-sulfonamide, -   (9)     4-methoxy-N,2,6-trimethyl-N-(2-(2-(6-((4-methylpiperazin-1-yl)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide, -   (10)     N-(3-(6-(morpholinomethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-3-oxo-1-phenylpropyl)naphthalene-2-sulfonamide, -   (11)     4-methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(6-(pyrrolidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (12)     4-methoxy-N,2,6-trimethyl-N-(2-(2-(6-(3-(4-methylpiperazin-1-yl)propyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide, -   (13)     N-(3-(6-(3-(4-methylpiperazin-1-yl)propyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-3-oxo-1-phenylpropyl)naphthalene-2-sulfonamide, -   (14)     N-(2-(2-(6-((dimethylamino)methyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide, -   (15)     4-methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(1-phenyl-6-(pyrrolidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (16)     4-methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(1-phenyl-6-(piperidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (17)     N-(2-(2-(6-((dimethylamino)methyl)-1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzene-sulfonamide, -   (18)     N-(2-(2-(1-tert-butyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzenesulfonamide, -   (19)     N-isobutyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-oxo-2-(1-(pyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (20)     N-(2-(2-(1-(6-chloropyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzenesulfonamide, -   (21)     N-(2-(2-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzenesulfonamide, -   (22)     N-isobutyl-4-methoxy-N-(2-(2-(1-(4-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-2,3,6-trimethylbenzenesulfonamide, -   (23)     N-isobutyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-oxo-2-(1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (24)     N-(2-(2-(1-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzenesulfonamide, -   (25)     N-isobutyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-oxo-2-(1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (26)     N-isobutyl-4-methoxy-N-(2-(2-(1-(3-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-2,3,6-trimethylbenzenesulfonamide, -   (27)     N-(2-(2-(1-tert-butyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethylbenzenesulfonamide, -   (28)     4-methoxy-N,2,3,5-tetramethyl-N-(2-(2-(1-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide, -   (29)     4-methoxy-N,2,3,5-tetramethyl-N-(2-(2-oxo-2-(1-(pyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (30)     N-(2-(2-(1-(6-chloropyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethylbenzenesulfonamide, -   (31)     4-methoxy-N-(2-(2-(1-(4-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,3,5-tetramethylbenzenesulfonamide, -   (32)     4-methoxy-N,2,3,5-tetramethyl-N-(2-(2-oxo-2-(1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (33)     N-(2-(2-(1-(3,4-difluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethylbenzenesulfonamide, -   (34)     N-(2-(2-(1-(3,4-dimethylphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethylbenzenesulfonamide, -   (35)     N-(2-(2-(1-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethylbenzenesulfonamide, -   (36)     4-methoxy-N,2,3,5-tetramethyl-N-(2-(2-oxo-2-(1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (37)     4-methoxy-N,2,3,5-tetramethyl-N-(2-(2-oxo-2-(1-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (38)     4-methoxy-N-(2-(2-(1-(3-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,3,5-tetramethylbenzenesulfonamide, -   (39)     N-(2-(2-(1-(2-fluoro-4-(trifluoromethyl)phenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethyl-benzenesulfonamide, -   (40)     N-benzyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-(1-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide, -   (41)     N-benzyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-oxo-2-(1-(pyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (42)     N-benzyl-N-(2-(2-(1-(6-chloropyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,3,6-trimethylbenzenesulfonamide, -   (43)     N-benzyl-N-(2-(2-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,3,6-trimethylbenzenesulfonamide, -   (44)     N-benzyl-N-(2-(2-(1-tert-butyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylbenzenesulfonamide, -   (45)     N-benzyl-4-methoxy-2,6-dimethyl-N-(2-(2-(1-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide, -   (46)     N-benzyl-N-(2-(2-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylbenzenesulfonamide, -   (47)     N-benzyl-4-methoxy-N-(2-(2-(1-(4-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-2,6-dimethylbenzenesulfonamide, -   (48)     N-benzyl-4-methoxy-2,6-dimethyl-N-(2-(2-oxo-2-(1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (49)     N-benzyl-N-(2-(2-(1-(3,4-dimethylphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylbenzenesulfonamide, -   (50)     N-benzyl-4-methoxy-2,6-dimethyl-N-(2-(2-oxo-2-(1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (51)     N-benzyl-N-(2-(2-(1-(4-tert-butylphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylbenzenesulfonamide, -   (52)     N-(2-(2-(1-tert-butyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide, -   (53)     4-methoxy-N,2,6-trimethyl-N-(2-(2-(1-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide, -   (54)     4-methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(1-(pyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (55)     N-(2-(2-(1-(6-chloropyridin-3-yl)-3,4-dihydropyrrolo-[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide, -   (56)     N-(2-(2-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide, -   (57)     N-(2-(2-(1-(3,4-difluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide, -   (58)     N-(2-(2-(1-(3,4-dimethylphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide, -   (59)     N-(2-(2-(1-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide, -   (60)     4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (61)     4-methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(1-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (62)     4-methoxy-N-(2-(2-(1-(3-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,6-trimethylbenzenesulfonamide, -   (63)     N-(2-(2-(1-(2-fluoro-4-(trifluoromethyl)phenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzene-sulfonamide, -   (64)     N-(2-(2-(1-(4-tert-butylphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide, -   (65)     N-(2-(2-(1-tert-butyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide, -   (66)     N,2,4,6-tetramethyl-N-(2-(2-(1-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide, -   (67)     N,2,4,6-tetramethyl-N-(2-(2-oxo-2-(1-(pyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (68)     N-(2-(2-(1-(6-chloropyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide, -   (69)     N-(2-(2-(1-(4-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide, -   (70)     N,2,4,6-tetramethyl-N-(2-(2-oxo-2-(1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (71)     N-(2-(2-(1-(3,4-difluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide, -   (72)     N-(2-(2-(1-(3,4-dimethylphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide, -   (73)     N-(2-(2-(1-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide, -   (74)     N,2,4,6-tetramethyl-N-(2-(2-oxo-2-(1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (75)     N,2,4,6-tetramethyl-N-(2-(2-oxo-2-(1-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (76)     N-(2-(2-(1-(3-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide, -   (77)     N-(2-(2-(1-(2-fluoro-4-(trifluoromethyl)phenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide, -   (78)     N-(2-(2-(1-(4-tert-butylphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide, -   (79)     N-(2-(2-(1-tert-butyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide, -   (80)     4-methoxy-N,2,3,6-tetramethyl-N-(2-(2-(1-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide, -   (81)     4-methoxy-N,2,3,6-tetramethyl-N-(2-(2-oxo-2-(1-(pyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (82)     N-(2-(2-(1-(6-chloropyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide, -   (83)     4-methoxy-N-(2-(2-(1-(4-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,3,6-tetramethylbenzenesulfonamide, -   (84)     4-methoxy-N,2,3,6-tetramethyl-N-(2-(2-oxo-2-(1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (85)     N-(2-(2-(1-(3,4-difluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide, -   (86)     N-(2-(2-(1-(3,4-dimethylphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide, -   (87)     N-(2-(2-(1-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide, -   (88)     4-methoxy-N,2,3,6-tetramethyl-N-(2-(2-oxo-2-(1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (89)     4-methoxy-N-(2-(2-(1-(3-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,3,6-tetramethylbenzenesulfonamide, -   (90)     N-(2-(2-(1-(4-tert-butylphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide, -   (91)     N-(2-(2-(6-((dimethylamino)methyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzene-sulfonamide, -   (92)     N-isobutyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-oxo-2-(1-phenyl-6-(pyrrolidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzene-sulfonamide, -   (93)     N-isobutyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-oxo-2-(1-phenyl-6-(piperidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzene-sulfonamide, -   (94)     N-isobutyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-(6-(morpholinomethyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzene-sulfonamide, -   (95)     N-(2-(2-(1-benzyl-6-((dimethylamino)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzene-sulfonamide, -   (96)     N-(2-(2-(6-((dimethylamino)methyl)-1-phenethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethyl-benzenesulfonamide, -   (97)     N-(2-(2-(1-butyl-6-((dimethylamino)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzene-sulfonamide, -   (98)     N-(2-(2-(6-((dimethylamino)methyl)-1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethyl-benzenesulfonamide, -   (99)     N-(2-(2-(6-((dimethylamino)methyl)-1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzene-sulfonamide, -   (100)     N-(2-(2-(1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzenesulfonamide, -   (101)     N-isobutyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-oxo-2-(1-propyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (102)     N-isobutyl-N-(2-(2-(1-isopropyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,3,6-trimethylbenzenesulfonamide, -   (103)     N-(2-(2-(1-ethyl-6-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzenesulfonamide, -   (104)     N-isobutyl-N-(2-(2-(1-isopropyl-6-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,3,6-trimethylbenzenesulfonamide, -   (105)     N-(2-(2-(6-((dimethylamino)methyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethylbenzene-sulfonamide, -   (106)     4-methoxy-N,2,3,5-tetramethyl-N-(2-(2-oxo-2-(1-phenyl-6-(pyrrolidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzene-sulfonamide, -   (107)     4-methoxy-N,2,3,5-tetramethyl-N-(2-(2-oxo-2-(1-phenyl-6-(piperidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzene-sulfonamide, -   (108)     4-methoxy-N,2,3,5-tetramethyl-N-(2-(2-(6-(morpholinomethyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide, -   (109)     N-(2-(2-(1-benzyl-6-((dimethylamino)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethylbenzene-sulfonamide, -   (110)     N-(2-(2-(6-((dimethylamino)methyl)-1-phenethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethylbenzene-sulfonamide, -   (111)     N-(2-(2-(1-butyl-6-((dimethylamino)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethylbenzene-sulfonamide, -   (112)     N-(2-(2-(6-((dimethylamino)methyl)-1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethylbenzene-sulfonamide, -   (113)     N-(2-(2-(6-((dimethylamino)methyl)-1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethylbenzenesulfonamide, -   (114)     N-(2-(2-(1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethylbenzenesulfonamide, -   (115)     4-methoxy-N,2,3,5-tetramethyl-N-(2-(2-oxo-2-(1-propyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (116)     N-benzyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-oxo-2-(1-phenyl-6-(pyrrolidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzene-sulfonamide, -   (117)     N-benzyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-(6-(morpholinomethyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzene-sulfonamide, -   (118)     N-benzyl-N-(2-(2-(1-benzyl-6-((dimethylamino)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,3,6-trimethylbenzene-sulfonamide, -   (119)     N-benzyl-N-(2-(2-(6-((dimethylamino)methyl)-1-phenethyl-3,4-dihydropyrrolo-[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,3,6-trimethylbenzene-sulfonamide, -   (120)     N-benzyl-N-(2-(2-(1-butyl-6-((dimethylamino)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)-ethyl)-4-methoxy-2,3,6-trimethyl-benzenesulfonamide, -   (121)     N-benzyl-N-(2-(2-(6-((dimethylamino)methyl)-1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,3,6-trimethylbenzene-sulfonamide, -   (122)     N-benzyl-N-(2-(2-(6-((dimethylamino)methyl)-1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethyl)ethyl)-4-methoxy-2,3,6-trimethylbenzenesulfonamide, -   (123)     N-benzyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-oxo-2-(1-propyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (124)     N-benzyl-N-(2-(2-(1-isopropyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,3,6-trimethylbenzenesulfonamide, -   (125)     N-benzyl-4-methoxy-2,6-dimethyl-N-(2-(2-oxo-2-(1-phenethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (126)     N-benzyl-N-(2-(2-(6-((dimethylamino)methyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylbenzenesulfonamide, -   (127)     N-benzyl-4-methoxy-2,6-dimethyl-N-(2-(2-oxo-2-(1-phenyl-6-(pyrrolidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzene-sulfonamide, -   (128)     N-benzyl-4-methoxy-2,6-dimethyl-N-(2-(2-oxo-2-(1-phenyl-6-(piperidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzene-sulfonamide, -   (129)     N-benzyl-N-(2-(2-(1-benzyl-6-((dimethylamino)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2-(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylbenzene-sulfonamide, -   (130)     N-benzyl-N-(2-(2-(6-((dimethylamino)methyl)-1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethyl-benzenesulfonamide, -   (131)     N-benzyl-N-(2-(2-(6-((dimethylamino)methyl)-1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylbenzene-sulfonamide, -   (132)     N-benzyl-N-(2-(2-(1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylbenzenesulfonamide, -   (133)     4-methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(1-phenethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (134)     N-(2-(2-(1-butyl-6-((dimethylamino)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide, -   (135)     N-(2-(2-(1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide, -   (136)     4-methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(1-propyl-3,4-dihydropyrrolo[1,2-a]-pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (137)     N-(2-(2-(1-isopropyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide, -   (138)     N-(2-(2-(1-ethyl-6-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide, -   (139)     N-(2-(2-(6-((dimethylamino)methyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide, -   (140)     N,2,4,6-tetramethyl-N-(2-(2-oxo-2-(1-phenyl-6-(pyrrolidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (141)     N,2,4,6-tetramethyl-N-(2-(2-oxo-2-(1-phenyl-6-(piperidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (142)     N,2,4,6-tetramethyl-N-(2-(2-(6-(morpholinomethyl)-1-phenyl-3,4-dihydro-pyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide, -   (143)     N-(2-(2-(1-benzyl-6-((dimethylamino)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide, -   (144)     N-(2-(2-(6-((dimethylamino)methyl)-1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide, -   (145)     N-(2-(2-(6-((dimethylamino)methyl)-1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide, -   (146)     N,2,4,6-tetramethyl-N-(2-(2-oxo-2-(1-propyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (147)     N-(2-(2-(1-isopropyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide, -   (148)     4-methoxy-N,2,3,6-tetramethyl-N-(2-(2-oxo-2-(1-phenethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (149)     4-methoxy-N,2,3,6-tetramethyl-N-(2-(2-oxo-2-(1-phenyl-6-(piperidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzene-sulfonamide, -   (150)     4-methoxy-N,2,3,6-tetramethyl-N-(2-(2-(6-(morpholinomethyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide, -   (151)     N-(2-(2-(1-benzyl-6-((dimethylamino)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzene-sulfonamide, -   (152)     N-(2-(2-(1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide, -   (153)     N-(2-(2-(1-isopropyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide, -   (154)     N-benzyl-4-methoxy-2,6-dimethyl-N-(2-(2-oxo-2-(1-propyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (155)     N-benzyl-N-(2-(2-(1-isopropyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylbenzenesulfonamide, -   (156)     N-(3-(6-(2-(4-methylpiperazin-1-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-3-oxo-1-phenylpropyl)naphthalin-2-sulfonamide, -   (157)     N-(3-(6-(2-morpholinoethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-3-oxo-1-phenylpropyl)naphthalin-2-sulfonamide, -   (158)     4-methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(6-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (159)     N-(3-oxo-1-phenyl-3-(6-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)propyl)naphthalene-2-sulfonamide, -   (160)     4-methoxy-N,2,6-trimethyl-N-(2-(2-(6-(2-(4-methylpiperazin-1-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide, -   (161)     4-methoxy-N,2,6-trimethyl-N-(2-(2-(6-(2-morpholinoethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide, -   (162)     N-((1R)-3-(1-Ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-3-oxo-1-phenylpropyl)naphthalene-2-sulfonamide, -   (163)     4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(3-(piperidin-1-ylmethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (164)     (R)-N-(3-oxo-1-phenyl-3-(3-(piperidin-1-ylmethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)propyl)naphthalene-2-sulfonamide, -   (165)     4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(6-(pyridin-4-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (166)     4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(6-(pyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (167)     N-(3-Oxo-1-phenyl-3-(6-(pyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)propyl)naphthalene-2-sulfonamide, -   (168)     N-(3-Oxo-1-phenyl-3-(6-(pyridin-4-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)propyl)naphthalene-2-sulfonamide, -   (169)     N-(3-Oxo-1-phenyl-3-(6-(pyridin-4-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)propyl)naphthalene-2-sulfonamide, -   (170)     4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(6-(2-(pyridin-3-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (171)     N-(3-Oxo-1-phenyl-3-(6-(2-(pyridin-3-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)propyl)naphthalene-2-sulfonamide, -   (172)     4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(6-(2-(pyridin-4-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (173)     N-(3-Oxo-1-phenyl-3-(6-(2-(pyridin-4-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)propyl)naphthalene-2-sulfonamide, -   (174)     4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(6-(pyridin-3-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (175)     4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(2-(pyridin-4-yl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (176)     N-(3-Oxo-1-phenyl-3-(6-(pyridin-3-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)propyl)naphthalene-2-sulfonamide, -   (177)     4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(6-(pyridin-4-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, -   (178)     4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(2-(2-(pyridin-4-yl)ethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethoxy)ethyl)benzenesulfonamide     and -   (179)     4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(2-(pyridin-4-ylmethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethoxy)ethyl)benzenesulfonamide     in the form of an individual enantiomer or an individual     diastereomer, in the form of the racemate, enantiomers,     diastereomers, mixtures of the enantiomers or diastereomers, in each     case in the form of their bases and/or physiologically compatible     salts.

The numbering adopted above of the individual embodiments of the compounds according to the invention is retained in the following discussions of the present invention, in particular in the description of the examples.

The compounds according to the invention exhibit an antagonistic action on the human B1R receptor or on the B1R receptor of rats. In a preferred embodiment of the invention the compounds according to the invention exhibit an antagonistic action on both the human B1R receptor (hB1R) and the B1R receptor of rats (rB1R).

Particularly preferred are compounds which at a concentration of 10 μM in the FLIPR assay exhibit an inhibition on the human B1R receptor and/or on the B1R receptor of rats of at least 15%, preferably at least 25%, more preferably at least 50%, still more preferably at least 70%, most preferably at least 80% and especially preferably at least 90%.

Particularly preferred are compounds that in a concentration of 10 μM exhibit an inhibition on the human B1R receptor and on the B1R receptor of rats of at least 70%, especially at least 80% and particularly preferably at least 90%.

The agonistic or antagonistic action of compounds can be quantified on the bradykinin 1 receptor (B1R) of humans and rats with ectopically expressing cell lines (CHO K1 cells) and with the aid of a Ca²⁺-sensitive dye (Fluo-4) in the fluorescent imaging plate reader (FLIPR). The figure in percent activation refers to the Ca²⁺ signal after addition of Lys-Des-Arg⁹-bradykinin (0.5 nM) and Des-Arg⁹-bradykinin (100 nM). Antagonists result in a suppression of the Ca²⁺ inflow after the addition of the agonist. Percent inhibition values are given in comparison to the maximum achievable inhibition.

The compounds according to the invention act, for example, on the Bradykinin 1 receptor (B1R), which is implicated in connection with various disorders or disease states, which means that they are useful as pharmaceutically active ingredients in pharmaceutical compositions (i.e., medicaments). The present invention therefore also provides medicaments containing at least one substituted sulfonamide compound according to the invention as well as optionally suitable additives and/or auxiliary substances and/or optionally further active substances. These medicaments are particularly suitable for treating pain, in particular acute, visceral, neuropathic, chronic pain and/or inflammatory pain. Moreover, these medicaments are also suitable for treating diabetes, diseases of the respiratory tract, inflammatory intestinal diseases, neurological diseases, inflammation of the skin, rheumatic diseases, septic shock, reperfusion syndrome, obesity, and as an angiogenesis inhibitor.

In addition to at least one substituted sulfonamide compound according to the invention, the medicaments according to the invention optionally also contain suitable additives and/or auxiliary substances, thus also carrier materials, fillers, solvents, diluents, colourants and/or binders, and can be administered as liquid medicament forms in the form of injections for solution, drops or juices, as semi-solid medicament forms in the form of granules, tablets, pellets, patches, capsules, plasters/spray plasters or aerosols. The choice of the auxiliary substances, etc. as well as the amounts thereof to be used depend on whether the medicament is to be administered orally, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, nasally, buccally, rectally or topically, for example to the skin, mucous membranes or to the eyes. For oral application suitable are preparations in the form of tablets, pills, capsules, granules, drops, juices and syrups, while for parenteral, topical and inhalative application suitable preparations are in the form of solutions, suspensions, easily reconstitutable dry preparations as well as sprays. Sulfonamide compounds according to the invention in depot form, in dissolved form or in a plaster, optionally with the addition of agents promoting penetration of the skin, are suitable percutaneous application preparations. Orally or percutaneously usable preparation forms can provide for the delayed release of the substituted sulfonamide compounds according to the invention. The substituted sulfonamide compounds according to the invention can also be used in parenteral long-term depot forms, such as for example implants or implanted pumps. In principle other active constituents known to the person skilled in the art can be added to the medicaments according to the invention.

The amount of active constituent to be administered to the patient varies depending on the patient's weight, type of application, medical indications and the severity of the illness. Normally 0.00005 to 50 mg/kg, in particular 0.01 to 5 mg/kg of at least one substituted sulfonamide compound according to the invention are administered.

In a preferred form of the medicament a contained substituted sulfonamide compound according to the invention may be present as a pure (isolated) diastereomer and/or enantiomer, as a racemate, or as a non-equimolar or equimolar mixture of the diastereomers and/or enantiomers.

B1R is involved in particular in the phenomenon of pain. Accordingly, the substituted sulfonamide compounds according to the invention can be used for the preparation of a medicament for treating pain, in particular acute, visceral, neuropathic or chronic pain. The invention accordingly also provides the use of a substituted sulfonamide compound according to the invention for the preparation of a medicament for treating pain, in particular acute, visceral, neuropathic or chronic pain. Moreover, the present invention also provides the use of a substituted sulfonamide compound according to the invention for the preparation of a medicament for the treatment of inflammatory pain.

The present invention also provides the use of a substituted sulfonamide compound according to the invention for the preparation of a medicament for treating diabetes, diseases of the respiratory tract, inflammatory intestinal diseases, neurological diseases, inflammation of the skin, rheumatic diseases, septic shock, reperfusion syndrome, obesity, and as an angiogenesis inhibitor.

In this connection it may be preferred in one of the above uses if an employed substituted sulfonamide compound is present as a pure diastereomer and/or enantiomer, as a racemate, or as a non-equimolar or equimolar mixture of the diastereomers and/or enantiomers.

The invention also provides a method for treating, in particular in one of the aforementioned medical indications, a non-human mammal or a person that requires treatment for pain, in particular chronic pain, by administration of a therapeutically active dose of a substituted sulfonamide compound according to the invention or a medicament according to the invention.

The invention also provides a method for treating, in particular in one of the aforementioned medical indications, a non-human mammal or a person that requires treatment thereof, by administration of a therapeutically active dose of a substituted sulfonamide compound according to the invention or a medicament according to the invention.

The invention also provides a method for the preparation of the substituted sulfonamide compounds according to the invention as explained and illustrated in the following description, examples as well as the claims.

General Process for Preparing Substituted Sulfonamide Compounds of the Invention:

The carboxylic acids N are converted in an amide formation using primary or secondary amines O in the presence of water-removing agents such as sodium or magnesium sulfate, phosphorus oxide or reagents such as for example CDI, DCC (optionally polymer-bound), TBTU, EDCI, PyBOP or PFPTFA, also in the presence of HOAt or HOBt and an organic base, for example DIPEA or pyridine, in an organic solvent such as THF, dichloromethane, diethyl ether, dioxane, DMF or acetonitrile, at temperatures from 0° C. to the reflux temperature, to form the final products corresponding to formula P. General Process for the Preparation of the Acids N

In Method I the racemic (R and S configuration) or enantiomer-pure (R or S configuration) aminoalcohols A are reacted in a sulfonylation with sulfonyl chlorides, bromides or pentafluorophenylate R¹SO₂X (X=Cl, Br, OPFP), optionally in the presence of an organic or inorganic base, for example potassium carbonate, sodium carbonate, sodium hydrogen carbonate, diisopropylethylamine, triethylamine, pyridine, dimethylaminopyridine, diethylamine or DBU, preferably in an organic solvent, for example acetone, acetonitrile, dichloromethane or tetrahydrofuran and at a temperature from 0° to the reflux temperature, to form the sulfonylated aminoalcohols B.

The sulfonylated aminoalcohols B are reacted in an alkylation reaction with halogenated ester compounds using tetrabutylammonium chloride or bromide or tetrabutylammonium hydrogen sulfate in a phase transfer reaction using an organic solvent such as THF, toluene, benzene or xylene and inorganic bases such as potassium hydroxide, sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate or in the presence of an organic or inorganic base, conventional inorganic bases being metal alcoholates such as sodium methanolate, sodium ethanolate, potassium tert-butylate, lithium or sodium bases such as lithium diisopropylamide, butyllithium, tert-butyllithium, sodium methylate or metal hydrides such as potassium hydride, lithium hydride, sodium hydride, conventional organic bases being diisopropylethylamine, triethylamine, in an organic solvent such as dichloromethane, THF or diethyl ether, at 0° C. to the reflux temperature, to form the products of the general structure C.

In Method II the racemic (R and S configuration) or enantiomer-pure (R or S configuration) aminoalcohols E are reacted in a sulfonylation with sulfonyl chlorides, bromides or pentafluorophenolate R¹SO₂X (X=Cl, Br, OPFP), optionally in the presence of an organic or inorganic base, for example potassium carbonate, sodium hydrogen carbonate, diisopropylethylamine, triethylamine, pyridine, dimethylaminopyridine, diethylamine or DBU, preferably in an organic solvent, for example acetone, acetonitrile, dichloromethane or tetrahydrofuran and at a temperature from 0° to the reflux temperature, to form the sulfonylated aminoalcohols F. The sulfonylated aminoalcohols F are then reacted in an alkylysation reaction with alkyl halides (RX, X=1, Br, Cl), mesylates or alternative alkylation reagents, optionally in the presence of an organic or inorganic base, for example sodium hydride, potassium carbonate, cesium carbonate, DBU or DIPEA, preferably in an organic solvent, for example dimethylformamide, acetone, THF, acetonitrile, dioxane or mixtures of these solvents, at a temperature from 0° C. to the reflux temperature, to form the sulfonylated aminoalcohols B.

In Method III the racemic (R and S configuration) or enantiomer-pure (R or S configuration) acids G are esterified using water-extracting reagents, for example inorganic acids such as H₂SO₄ or phosphorus oxides or organic reagents such as thionyl chloride, in organic solvents such as THF, diethyl ether, methanol, ethanol or dichloromethane, to the stage H, at temperatures from room temperature to reflux temperatures. The amino acid esters H are reacted in a sulfonylation with sulfonyl chlorides, bromides or pentafluorophenolate R¹SO₂X (X=Cl, Br, OPFP), optionally in the presence of an organic or inorganic base, for example potassium carbonate, sodium carbonate, sodium hydrogen carbonate, diisopropylethylamine, triethylamine, pyridine, dimethylaminopyridine, diethylamine or DBU, preferably in an organic solvent, for example acetone, acetonitrile, dichloromethane or tetrahydrofuran and at a temperature from 0° C. to the reflux temperature, to form the sulfonylated aminoesters I.

In the Methods I-III the ester compounds C and I are reacted in an ester cleavage using organic acids such as trifluoroacetic acid or aqueous inorganic acids such as hydrochloric acid, or using aqueous inorganic bases such as lithium hydroxide, potassium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate in organic solvents such as methanol, dioxane, dichloromethane, THF, diethyl ether or mixtures of these solvents, at 0° C. to room temperature, to form the acid stages corresponding to formula D (acid building blocks S1-S8).

General Processes for Preparing the Amines O

Pyrrole A is dissolved in a suitable solvent, such as for example ethanol, methanol, 2-butanone, DMSO, diethyl ether, water, benzene, toluene, THF, DCM, acetonitrile, acetone, DMF or pentane or a mixture of these solvents, and a suitable base is added, such as for example potassium hydroxide, sodium hydroxide, optionally in aqueous or alcoholic solution, potassium carbonate, potassium hexamethyldisilazane, sodium hydride, potassium hydride, sodium methanolate, sodium ethanolate, sodium tert. butylate or diisopropylethylamine, optionally with the addition of an auxiliary substance such as for example 18-crown-6,15-crown-5, tetrabutylammonium bromide or sulfate, benzyltriethylammonium chloride, 1-n-butyl-3-methylimidazolium tetrafluoroborate or DMAP, followed by reaction with the corresponding iodide, bromide or chloride compound to form the stage B.

The ring closure to form the 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine C is carried out by reacting the 2-(1H-pyrrol-1-yl)ethanamine with the corresponding aldehyde in solvents such as acetic acid, ethanol, methanol, pyridine, benzene, toluene, DCM or a mixture of these solvents, optionally with the addition of benzotriazole, aluminium trichloride or p-toluenesulfonic acid and optionally with removal by azeotropic distillation of the water formed in the reaction. The reaction times can be between 1 and 48 hours and the reaction temperature can vary between 20° C. and 110° C.

The ring closure to form the 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine stage C can however also be achieved by reacting the 2-(1H-pyrrol-1-yl)ethanamine with the corresponding carboxylic acid followed by reduction of the initially formed cyclic imine D with reducing agents, such as for example sodium boron hydride.

Starting from 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines, for further derivatisations on the pyrrole part the nitrogen in the piperidine part must if necessary be protected. Various protective groups are suitable for this purpose, such as for example BOC, Cbz or Fmoc protective groups.

The introduction of the BOC protective group by means of di-tert.-butyl dicarbonate can be carried out in solvents such as for example dioxane, DCM, THF, DMF, water, benzene, toluene, methanol, acetonitrile or mixtures of these solvents, optionally with the addition of sodium hydroxide, triethylamine, diisopropylethylamine, sodium hydrogen carbonate, sodium carbonate or DMAP at temperatures between 0° C. and 100° C. The Cbz protective group can be introduced by reacting benzyl chloroformate in solvents such as for example diethyl ether, THF, DMF, benzene, toluene, dioxane, water, acetone, ethyl acetate, DCM or chloroform, optionally with the addition of a base such as for example sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide or triethylamine, optionally with the addition of a coupling reagent, such as for example HOBt. The Fmoc protective group is introduced by reacting 9H-fluoren-9-yl methylchloroformate in solvents such as for example DCM, DCE, diethyl ether, THF, dioxane, acetone, acetonitrile, DMF or water, optionally with the addition of a base, such as for example diisopropylethylamine, triethylamine, pyridine, N-methylmorpholine, sodium carbonate or sodium hydrogen carbonate and optionally under microwave irradiation.

The introduction of the amino methyl substituent on the pyrrole ring is carried out via an aminoalkylation to form the stages F. For the aminoalkylation the corresponding aromatic compound can be reacted with formaldehyde and the corresponding amine in ethanol or methanol. A variant of this process uses the reaction of an iminium salt with the corresponding aromatic system to form the stage E. The iminium salt is obtained for example by cleavage of the corresponding aminal.

The aminal is formed by reacting the corresponding amine with formaldehyde. The reaction can be carried out in solvents such as for example water, methanol, ethanol, tert.-butanol, benzene, toluene, diethyl ether, dioxane, THF, chloroform, DCM, DMF, acetonitrile, dilute aqueous HCl solution or mixtures of these solvents, optionally with the addition of a base, such as for example potassium carbonate or sodium hydroxide.

The iminium salt is obtained by reacting the aminal with for example acetyl or benzoyl chloride, mesyl chloride, trimethylsilyl chloride or iodide, tetrachlorosilane or borone trifluoride etherate, in solvents such as for example carbon tetrachloride, chloroform, DCM, diethyl ether, DMF, acetonitrile, hexane or DME at a temperature between −80° C. and +25° C.

The subsequent aminoalkylation to the stages F can be carried out in solvents such as for example acetonitrile, THF, DCM, diethyl ether, toluene or benzene at temperatures between −78° C. and room temperature.

The aminoalkylated 5,6,7,8-tetrahydropyrrolo[1,2-a]pyrazine compound G used as building block is obtained by cleavage of the corresponding protective group.

BOC protective groups can be removed, for example, by reaction with HCl in organic solvents such as dioxane, methanol, ethanol, acetonitrile or ethyl acetate, or by reaction with TFA or methanesulfonic acid in dichloromethane or THF, at a temperature from 0° C. to 110° C. and a reaction time of 0.5 to 20 hours.

The Cbz protective group can be removed, for example, under acidic conditions. This acidic cleavage can be carried out for example by reaction with an HBr/glacial acetic acid mixture, a mixture of TFA in dioxane/water or HCl in methanol or ethanol. Also suitable however are reagents such as for example Me₃Sil in solvents such as for example DCM, chloroform or acetonitrile, BF₃ etherate with the addition of ethanethiol or Me₂S in solvents such as for example DCM, a mixture of aluminium chloride/anisole in a mixture of DCM and nitromethane, or triethylsilane/PdCl₂ in methanol with the addition of triethylamine. A further method is the hydrogenolytic cleavage of the protective group at elevated pressure or without the use of pressure, by means of catalysts such as for example Pd on charcoal, Pd(OH)₂, PdCl₂, Raney nickel or PtO₂ in solvents such as for example methanol, ethanol, 2-propanol, THF, acetic acid, ethyl acetate, chloroform, optionally with the addition of HCl, formic acid or TFA.

The Fmoc protective group is as a rule removed under basic conditions in solvents such as for example acetonitrile, DMF, THF, diethyl ether, methanol, ethanol, 1-octanethiol, DMC or chloroform. Suitable bases are for example diethylamine, piperidine, 4-aminomethylpiperidine, pyrrolidine, DBU, NaOH or LiOH. Reagents such as for example Ag₂O/Mel can however also be used.

Starting from the protected 1,2,3,4-tetrahydropyrrolo[1,2]a]pyrazine E an aldehyde function is first of all introduced in the pyrrole ring in a Vilsmeier reaction. The Vilsmeier reaction is carried out by reacting HCN and HCl in CHCl₃ or diethyl ether or a mixture of these solvents. Further suitable reagents for the Vilsmeier reaction are DMF and oxalyl chloride or POCl₃ in solvents such as for example DCM or DCE, but also for example trimethoxyethane and TiCl₄ in DCM. N-(chloromethylene)-N-methylmethane aminium chloride with the addition of NaOH can also be used.

The subsequent Wittig reaction to the stages I, using phosphorylidene and a strong base, for example potassium tert.-butylate, n-butyllithium, s-butyllithium, phenyllithium, lithium diisopropylamide or lithium hexamethyldisilazide in organic solvents such as THF, diethyl ether, cyclohexane, toluene or a mixture of these solvents at a temperature from −78° C. to +30° C. yields the corresponding unsaturated esters.

The reduction of the double bond can be carried out hydrogenolytically or by adding suitable reducing agents. Heterogeneous catalysts as well as homogeneous catalysts can be used in the hydrogenolysis. Suitable heterogeneous catalysts are for example Pd on charcoal or Raney nickel in solvents such as for example methanol, ethanol, toluene, THF, ethyl acetate, acetic acid or in mixtures of these solvents, optionally with the addition of bases such as for example triethylamine. The reaction can be carried out at atmospheric pressure or at elevated pressure. A suitable homogeneous catalyst is for example (PPh₃)₃RhCl in benzene or toluene. A suitable reducing agent is for example NaBH₄ with the addition of NiCl₂ in the solvents such as for example methanol, ethanol, THF or mixtures of these solvents.

The reduction of the ester group for the preparation of the stages K can be carried out by reduction with reducing agents such as for example DIBAHL-H in solvents such as for example THF, DCM, toluene or hexane at temperatures between −78° C. and room temperature.

In the subsequent reductive amination to the stages L the aldehyde is reacted with an amine and the imine thereby formed is then reduced to the amine. Suitable reducing agents are for example NaBH₄, NaBH(OAc)₃, NaCNBH₃, NH₄CNBH₃, polymer-bound cyanoboron hydride, borane-pyridine complex or triethylsilane. The reaction can be carried out in solvents such as for example methanol, ethanol, DCM, DCE, acetonitrile, THF, toluene, water, DMSO, DMF, 1-methyl-2-pyrrolidin-2-one or mixtures of these solvents. Auxiliary reagents such as for example HCl (gaseous or as an aqueous solution), acetic acid, TFA, ZnCl₂, 1,3-dimethyl-2-imidazolidine, MgSO₄, Na₂SO₄ or molecular sieves are also used. The imine that is formed can however also be converted to the amine by catalytic hydrogenation on catalysts such as for example PtO₂ or Pd/C in solvents such as for example methanol or ethanol.

The compound M used as building block is obtained by cleavage of the corresponding protective group. BOC protective groups can be eliminated, for example, by reaction with HCl in organic solvents such as dioxane, methanol, ethanol, acetonitrile or ethyl acetate, or by reaction with TFA or methanesulfonic acid in dichloromethane or THF at a temperature from 0° C. to 110° C. and a reaction time of 0.5 to 20 hours. The Cbz protective group can be removed, for example, under acidic conditions. This acidic cleavage can be carried out for example by reaction with an HBr/glacial acetic acid mixture, a mixture of TFA in dioxane/water or HCl in methanol or ethanol. Also suitable however are reagents such as for example Me₃Sil in solvents such as for example DCM, chloroform or acetonitrile, BF₃ etherate with the addition of ethanethiol or Me₂S in solvents such as for example DCM, a mixture of aluminium chloride/anisole in a mixture of DCM and nitromethane or triethylsilane/PdCl₂ in methanol with the addition of triethylamine. A further method is the hydrogenolytic cleavage of the protective group at elevated pressure or without the use of pressure with the aid of catalysts such as for example Pd on charcoal, Pd(OH)₂ PdCl₂, Raney nickel or PtO₂ in solvents such as for example methanol, ethanol, 2-propanol, THF, acetic acid, ethyl acetate, chloroform, optionally with the addition of HCl, formic acid or TFA. The Fmoc protective group is as a rule removed under basic conditions in solvents such as for example acetonitrile, DMF, THF, diethyl ether, methanol, ethanol, 1-octanethiol, DCM or chloroform. Suitable bases are for example diethylamine, piperidine, 4-aminomethylpiperidine, pyrrolidine, DBU, NaOH or LiOH. Reagents such as for example Ag₂O/Mel can however also be used.

The nitrogen on the piperidine part of the alkyl 5,6,7,8-tetrahydroimidazo[1,2]a]-pyrazin-2-carboxylate of stage A first of all has to be protected for further reactions. Various protective groups, such as for example the BOC, Cbz or Fmoc protective group, are suitable for this purpose. The introduction of the BOC protective group by means of di-tert.-butyl dicarbonate can be carried out in solvents such as for example dioxane, DCM, THF, DMF, water, benzene, toluene, methanol, acetonitrile or mixtures of these solvents, optionally with the addition of sodium hydroxide, triethylamine, diisopropyl-ethylamine, sodium hydrogen carbonate, sodium carbonate or DMAP at temperatures between 0° C. and 100° C. The Cbz protective group can be introduced by the reaction of benzyl chloroformate in solvents such as for example diethyl ether, THF, DMF, benzene, tolulene, dioxane, water, acetone, ethyl acetate, DCM or chloroform, optionally with the addition of a base, such as for example sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide or triethylamine, optionally with the addition of a coupling reagent such as for example HOBt. The Fmoc protective group is introduced by reacting 9H-fluoren-9-yl methylchloroformate in solvents such as for example DCM, DCE, diethyl ether, THF, dioxane, acetone, acetonitrile, DMF or water, optionally with the addition of a base, such as for example diisopropylethylamine, triethylamine, pyridine, N-methylmorpholine, sodium carbonate or sodium hydrogen carbonate and optionally under microwave irradiation.

The reduction of the ester group for the preparation of the stages C can be carried out by reduction with reducing agents such as for example DIBAHL-H in solvents such as for example THF, DCM, toluene or hexane at temperatures between −78° C. and room temperature.

In the subsequent reductive amination for the preparation of the stages D, the aldehyde is reacted with an amine and the formed imine is then reduced to the amine.

Suitable reducing agents are for example NaBH₄, NaBH(OAc)₃, NaCNBH₃, NH₄CNBH₃, polymer-bound cyano boron hydride, borane-pyridine complex or triethylsilane. The reaction can be carried out in solvents such as for example methanol, ethanol, DCM, DCE, acetonitrile, THF, toluene, water, DMSO, DMF, 1-methyl-2-pyrrolidin-2-one or mixtures of these solvents. Often auxiliary reagents such as for example HCl (gaseous or as an aqueous solution), acetic acid, TFA, ZnCl₂, 1,3-dimethyl-2-imidazolidine, MgSO₄, Na₂SO₄ or molecular sieves are also used. The formed imine can however also be converted to the amine by catalytic hydrogenation on catalysts such as for example PtO₂ or Pd/C in solvents such as for example methanol or ethanol.

The aminoalkylated compound E used as building block is obtained by cleavage of the corresponding protective group. BOC protective groups can be removed, for example, by reaction with HCl in organic solvents such as dioxane, methanol, ethanol, acetonitrile or ethyl acetate, or by reaction with TFA or methanesulfonic acid in dichloromethane or THF at a temperature from 0° C. to 110° C. and a reaction time of 0.5 to 20 hours. The Cbz protective group can be removed, for example, under acidic conditions. This acidic cleavage can be carried out for example by reaction with an HBr/glacial acetic acid mixture, a mixture of TFA in dioxane/water or HCl in methanol or ethanol. Also suitable however are reagents such as for example Me₃Sil in solvents such as for example DCM, chloroform or acetonitrile, BF₃ etherate with addition of ethanethiol or Me₂S in solvents such as for example DCM, a mixture of aluminium chloride/anisole in a mixture of DMC and nitromethane, or triethylsilane/PdCl₂ in methanol with the addition of triethylamine. A further method is the hydrogenolytic cleavage of the protective group at elevated pressure or without pressure with the aid of catalysts such as for example Pd on charcoal, Pd(OH)₂, PdCl₂, Raney nickel or PtO₂ in solvents such as for example methanol, ethanol, 2-propanol, THF, acetic acid, ethyl acetate, chloroform, optionally with the addition of HCl, formic acid or TFA. The Fmoc protective group is, as a rule, removed under basic conditions in solvents such as for example acetonitrile, DMF, THF, diethyl ether, methanol, ethanol, 1-octanethiol, DCM or chloroform. Suitable bases are for example diethylamine, piperidine, 4-aminomethylpiperidine, pyrrolidine, DBU, NaOH or LiOH. Reagents such as for example Ag₂O/Mel can however also be used.

Pharmacological Investigations

1. Functional Investigation on the Bradykinin 1 Receptor (B1R)

The agonistic or antagonistic action of substances can be determined on the bradykinin 1 receptor (B1R) of humans and rats by means of the following assay.

According to this assay the Ca²⁺ inflow through the channel is quantified by means of a Ca²⁺-sensitive dye (Fluo-4 type, Molecular Probes Europe BV, Leiden, Netherlands), in a Fluorescent Imaging Plate Reader (FLIPR, Molecular Devices, Sunnyvale, USA). Method:

Chinese hamster ovary cells (CHO K1 cells) are used, which are stably transfected with the human B1R gene (hB1R cells, Euroscreen s.a., Gosselies, Belgium), or with the B1R gene of rats (rB1R cells, Axxam, Milan, Italy). For functional investigations these cells are plated out on black 96-well plates with a clear floor (BD Biosciences, Heidelberg, Germany) in a density of 20,000/25,000 cells/well. The cells are incubated overnight with 10 vol. % FBS (foetal bovine serum, Gibco Invitrogen GmbH, Karlsruhe, Germany) at 37° C. and 5% CO₂ in a culture medium (hB1R cells: Nutrient Mixture Ham's F12, Gibco Invitrogen GmbH, Karlsruhe, Germany; rB1R cells: D-MEM/F12, Gibco Invitrogen GmbH, Karlsruhe, Germany). The following day the cells are charged for 60 minutes at 37° C. with 2.13 μM Fluo-4 (Molecular Probes Europe BV, Leiden, Netherlands) in HBSS buffer (Hank's buffered saline solution, Gibco Invitrogen GmbH, Karlsruhe, Germany) together with 2.5 M probenecid (Sigma-Aldrich, Taufkirchen, Germany) and 10 mM HEPES (Sigma-Aldrich, Taufkirchen, Germany).

The plates are then washed twice with HBSS buffer and HBSS buffer is added which additionally contains 0.1% BSA (bovine serum albumin; Sigma-Aldrich, Taufkirchen, Germany), 5.6 mM glucose and 0.05% gelatin (Merck KGaA, Darmstadt, Germany). After further incubation for 20 minutes at room temperature the plates are used for the Ca²⁺ measurement in the FLIPR. The Ca²⁺-dependent fluorescence is measured both before and after the addition of substances (λ_(ex)=488 nm, λ_(em)=540 nm). The quantification is carried out by measuring the highest fluorescence intensity (FC, fluorescence counts) over time.

FLIPR Assay:

The FLIPR protocol consists of two substance additions. First of all test substances (10 μM) are pipetted onto the cells and the Ca²⁺ inflow is compared with the control (hB1R: Lys-Des-Arg9-bradykinin 0.5 nM; rB1R: Des-Arg9-bradykinin 100 nM). This gives the result in percent activation referred to the Ca²⁺ signal after addition of Lys-Des-Arg9-bradykinin (0.5 nM), bzw. Des-Arg9-bradykinin (100 nM). After 10 minutes' incubation 0.5 nM Lys-Des-Arg9-bradykinin (hB1R) and 100 nM Des-Arg⁹-bradykinin (rB1R) are applied and the inflow of Ca²⁺ is likewise determined. Antagonists lead to a suppression of the Ca²⁺ inflow. The percent inhibition compared to the maximum achievable inhibition is calculated. The compounds show a good activity on both human and rat receptors.

The invention will be described in further detail hereinafter with reference to illustrative examples, which do not, however, restrict the scope of the invention.

EXAMPLES

List of Abbreviations:

-   Eq. Equivalent(s) -   Boc₂O Di-tert.-butyl dicarbonate -   CDI 1,1′-carbonyl diimidazole -   d Day(s) -   DCE 1,2-dichloroethane -   DCM Dichloromethane -   DIBAL-H Diisobutyl aluminium hydride -   DIPEA Diisopropylethylamine -   DMF Dimethylformamide -   DMAP 4-Dimethylaminopyridine -   EDCI N-(3-Dimethylaminopropyl)-N′-ethyl-carbodiimide -   wt. % Weight percent -   h Hour(s) -   HATU O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium     hexafluorophosphate -   HOAt 1-hydroxy-7-azabenzotriazole -   HOBt 1-hydroxy-1H-benzotriazole -   i.vac. In vacuo -   M Molar -   mbar Millibar -   min Minute(s) -   N Normal -   NaOH Sodium hydroxide -   RT Room temperature -   B.p. Boiling point -   THF Tetrahydrofuran -   TFA Trifluoroacetic acid -   Ms Methanesulfonyl

The following acid building blocks were used for the synthesis of the sulfonamide compounds according to the invention:

Acid building block Structure Name S1

{2-[(4-methoxy-2,6-dimethyl-benzenesulfonyl)-methyl- amino]-ethoxy}acetic acid S2

{2-[methyl-(2,4,6-trimethyl-benzenesulfonyl)-amino]- ethoxy}acetic acid S3

{2-[(4-methoxy-2,3,6-trimethyl-benzenesulfonyl)-methyl- amino]-ethoxy}acetic acid S4

{2-[benzyl-(4-methoxy-2,3,6-trimethyl-benzenesulfonyl)- amino]-ethoxy}acetic acid S5

2-[benzyl-(4-methoxy-2,6-dimethyl-benzenesulfonyl)- amino]-ethoxy}acetic acid S6

2-((4-methoxy-N,2,3,5- tetramethylphenylsulfonamido)methoxy)acetic acid S7

2-(2-(N-isobutyl-4-methoxy-2,3,6- trimethylphenylsulfonamido)ethoxy)acetic acid S8

3-(naphthalene-2-sulfonamido)-3-phenylpropionic acid S9

(R)-3-(Naphthalene-2-sulfonamido)-3- phenylpropanoic acid

Preparation of {2-[(4-methoxy-2,6-dimethyl-benzenesulfonyl)-methyl-amino]-ethoxy}acetic Acid S1

-   Stage 1. A solution of 3,5-dimethylanisole (102.5 g, 753 mmole) in     DCM (1000 ml) was cooled to 0° C. A solution of chlorosulfonic acid     (251 ml, 3763 mmole) in DCM (250 ml) was added dropwise to this     solution. After 10 minutes' reaction time the reaction solution was     poured into an icebath (1000 ml), and the phases were separated and     extracted again with DCM (250 ml). The combined organic phases were     washed with water (1000 ml) and satd. NaCl solution (1000 ml), dried     over Na₂SO₄ and concentrated by evaporation. The product was     purified by column chromatography on silica gel (heptane/DCM 5:1).     Yield: 63.5 g, 36%. -   Stage 2. 2-(methylamino)ethanol (3.8 ml), 46.9 mmole) was dissolved     in DCM (200 ml) and triethylamine (15 ml, 107 mmole) was added. The     solution was cooled to 0° C., a solution of     4-methoxy-2,6-dimethylbenzene-1-sulfonyl chloride (10 g, 42.6 mmole)     dissolved in DCM (100 ml) was added, and the whole was stirred for     1.5 hours at RT. After completion of the reaction HCl (0.5 M,     100 ml) was added, the phases were separated, washed with water,     dried over Na₂SO₄ and concentrated by evaporation. The crude product     was used without further purification in the next stage. Yield 12.2     g, >100%. -   Stage 3. n-Bu₄NCl (3.95 g, 14.2 mmole) was added to a solution of     N-2-(hydroxyethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide (12.2     max. 42.6 mmole) in toluene (250 ml). The reaction solution was     cooled to 0° C. and NaOH solution (35%, 250 ml) was added.     Tert.-butyl bromoacetate (9.3 ml, 63.9 mmole) was added dropwise to     this solution and then stirred for 3 hours at RT. The organic phase     was separated and washed three times with water (300 ml), dried over     Na₂SO₄ and concentrated by evaporation. The crude product was used     without further purification in the next stage. Yield 17.95 g,     >100%. -   Stage 4. The tert.-butyl     2-(2-(4-methoxy-N,2,6-trimethylphenylsulfonamido)ethoxy)-acetate     (17.95 g, max. 42.6 mmole) was stirred in a solution of TFA (30 ml)     and DCM (200 ml) for 2 hours at RT. After completion of the reaction     the solvent was removed on a rotary evaporator and the remaining TFA     was removed by evaporating twice with toluene and once with     diisopropyl ether. Yield: 13.6 g, 96% over 3 stages.

Preparation of {2-[methyl-(2,4,6-trimethyl-benzenesulfonyl)-amino]-ethoxy}acetic Acid S2

-   Stage 1. 2-(methylamino)ethanol (6.4 ml, 79.8 mmole) was dissolved     in DMC (500 ml) and triethylamine (13.3 ml, 95.9 mmole) was added.     The solution was cooled to 0° C. and a solution of     2,3,6-trimethylbenzene-1-sulfonyl chloride (21 g, 95.9 mmole)     dissolved in DCM (65 ml) was added dropwise, and the whole was     stirred for 4 hours at RT. After completion of the reaction the     reaction mixture was washed first with water and then with sodium     carbonate solution, and the phases were separated and extracted     three times with DCM. The combined organic phases were dried over     Na₂SO₄ and concentrated by evaporation. The crude product was     purified by column chromatography (silica gel, diethyl ether/hexane     9:1). -   Stage 2. Tetra-n-butylammonium hydrogen sulfate (2.24 g, 6.6 mmole)     was added to a solution of     N-(2-hydroxyethyl)-N,2,4,6-tetramethylbenzenesulfonamide (16.9 g, 66     mmole) in toluene (450 ml) and cooled to 0° C. NaOH solution (50%,     445 ml) was then added, followed by the dropwise addition of     tert.-butyl bromoacetate (20.3 ml, 138.5 mmole). The mixture was     then stirred for 3.5 hours at RT, following which the aqueous phase     was separated and extracted twice with diethyl ether (450 ml). The     combined organic phases were dried over Na₂SO₄, concentrated by     evaporation in vacuo, and the residue was purified by column     chromatography on silica gel (ethyl acetate). Yield: 15.2 g, 62%. -   Stage 3. Tert-butyl     (2-(2-(N,2,4,6-tetramethylphenylsulfonamido)ethoxy)acetate (15.2 g,     41 mmole) was stirred for 4 hours at RT in a solution of TFA (63 ml)     and DCM (290 ml). After completion of the reaction the solvent was     removed on a rotary evaporator and the remaining TFA was removed by     evaporating twice with toluene (200 ml).

Preparation of {2][4-methoxy-2,3,6-trimethyl-benzenesulfonyl)-methyl-amino]-ethoxy}acetic Acid S3

-   Stage 1. A solution of 4-methoxy-2,3,6-trimethylbenzenesulfonyl     chloride (2.29 g, 9.19 mmole) in THF (30 ml) was added dropwise at     0° C. to a solution of 2-methylaminoethanol (0.95 ml, 11.8 mmole)     and triethylamine (5 ml) in THF (15 ml). The mixture was then     stirred for 5 hours at RT, concentrated by evaporation in vacuo, and     the residue was taken up in NaHCO₃ solution and extracted with ethyl     acetate (3×30 ml). The combined organic phases were dried with     Na₂SO₄ and concentrated by evaporation in vacuo. Yield: 2.38 g, 90%. -   Stage 2. NaOH solution (35%, 40 ml) was added at 0° C. to a solution     of     N-(2-hydroxyethyl)-4-methoxy-2,3,6,N-tetramethylbenzenesulfonamide     (2.34 g, 8.2 mmole) and tetra-n-butylammonium hydrogen sulfate (611     mg, 1.8 mmole) in toluene (40 ml). A solution of tert.-butyl     bromoacetate (1.82 ml, 12.3 mmole) in toluene (35 ml) was then added     dropwise to the vigorously stirred two-phase system. The mixture was     then stirred for 2 hours at RT, following which the aqueous phase     was separated and the organic phase was washed neutral with water     (3×40 ml). The organic phase was dried with Na₂SO₄, concentrated by     evaporation in vacuo and the residue was purified by flash     chromatography with ethyl acetate/cyclohexane (1:3). Yield: 2.50 g,     76%. -   Stage 3. Triethylsilane (1.54 ml, 9.6 mmole) followed by TFA (5 ml)     were added to a solution of     {2-[(4-methoxy-2,3,6-trimethylbenzenesulfonyl)-methylamino]-ethoxy}acetic     acid tert-butyl acetate (2.48 g, 6.18 mmole) in DCM (50 ml), and the     whole was stirred for 5 hours at RT. The mixture was then     concentrated by evaporation in vacuo and the residue was taken up     several times in toluene and concentrated by evaporation each time.     The crude product was dissolved in ethyl acetate and extracted with     5% NaHCO₃ solution (3×50 ml). The combined organic phases were     adjusted to pH 1 with conc. hydrochloric acid and re-extracted with     ethyl acetate (3×50 ml). The combined organic phases were dried with     Na₂SO₄ and concentrated by evaporation in vacuo. Yield 2.41 g, >99%.

Preparation of {2-[benzyl-(4-methoxy-2,3,6-trimethyl-benzenesulfonyl)-amino]-ethoxy}acetic Acid S4

-   Stage 1. Triethylamine (11.2 ml, 80 mmole) was added to a solution     of 2-benzylaminoethanol (5.28 g, 35 mmole) in DCM (200 ml) and     cooled using an icebath. 4-methoxy-2,3,6-trimethylbenzene-1-sulfonyl     chloride (7.9 g, 32 mmole) was then added and stirred for 3 hours at     RT. After adding hydrochloric acid (0.5 M, 100 ml) the organic phase     was separated, washed with water, dried over Na₂SO₄, filtered, and     the solvent was distilled off. The crude product was used without     further purification. -   Stage 2. n-Bu₄NCl (2.78 g, 10 mmole) was added to a solution of     tert.-butyl bromoacetate (6.5 ml, 45 mmole) in toluene (125 ml),     cooled to 0° C., and then aqueous 35% NaOH (150 ml) was added     followed by the dropwise addition of     N-benzyl-N-(2-hydroxyethyl)-4-methoxy-2,3,6-trimethylbenzenesulfonamide     (10.8 g, 30 mmole) dissolved in toluene (25 ml). The reaction     mixture was stirred for 3 hours, then washed with water until     neutral, dried with Na₂SO₄, and the organic solvent was distilled     off. The crude product was used without further purification. -   Stage 3. The tert.-butyl     2-(2-N-benzyl-4-methoxy-2,6-dimethylphenylsulfonamido)-ethoxy)acetate     (14.3 g, 30 mmole) was dissolved in DCM (200 ml), TFA (30 ml) was     added, and the reaction mixture was stirred for 2 hours at RT. The     solvent was largely distilled off. The residue was taken up in     toluene (300 ml) and concentrated by evaporation on a rotary     evaporator. The crude product was purified by washing with     diisopropyl ether.

Preparation of {2-[benzyl-(4-methoxy-2,6-dimethyl-benzenesulfonyl)-amino]-ethoxy}acetic Acid S5

-   Stage 1. Triethylamine (11.2 ml, 80 mmole) was added to a solution     of 2-benzylaminoethanol (5.28 g, 35 mmole) in DCM (200 ml) and     cooled using an icebath. 4-methoxy-2,6-dimethylbenzene-1-sulfonyl     chloride (7.5 g, 32 mmole) was then added and stirred for 5 hours at     RT. After adding hydrochloric acid (0.5 M, 100 ml) the organic phase     was separated, washed with water, dried over Na₂SO₄, filtered, and     the solvent was distilled off. The crude product was used without     further purification. -   Stage 2. n-Bu₄NCl (2.78 g, 10 mmole) was added to a solution of     tert.-butyl bromoacetate (6.5 ml, 45 mmole) in toluene (125 ml),     cooled to 0° C., and aqueous 35% NaOH (150 ml) was first added,     followed by the dropwise addition of     N-benzyl-N-(2-hydroxyethyl)-4-methoxy-2,6-dimethylbenzenesulfonamide     (10.4 g, 30 mmole) dissolved in toluene (25 ml). The reaction     mixture was stirred for 3 hours, then washed with water till     neutral, dried with Na₂SO₄, and the organic solvent was distilled     off. The crude product was used without further purification. -   Stage 3. The tert.-butyl     2-(2-N-benzyl-4-methoxy-2,6-dimethylphenylsulfonamido)-ethoxy)acetate     (19.4 g, 41.8 mmole) was dissolved in a mixture of methanol (150     ml), THF (165 ml) and aqueous NaOH solution (6 M, 150 ml, 900 mmole)     and stirred for 1 hour at RT. After completion of the reaction the     solution was concentrated and HCl (6 M, 155 ml) was added at 0° C.     The aqueous phase was extracted with ethyl acetate (2×150 ml) and     the combined organic phases were dried over Na₂SO₄ and concentrated.     Yield: 17.05 g, 100%.

Preparation of 2-((4-methoxy-N,2,3,5-tetramethylphenylsulfonamido)-methoxy)acetic Acid S6

-   Stage 1. K₂CO₃ (102 g, 740 mmole) and methyl iodide (55.3 ml, 888     mmole) were added to a solution of 2,3,6-trimethylphenol (80.6 g,     740 mmole) in DMSO (90 ml) and stirred for 2 days at RT. The     reaction mixture was added to water (750 ml) and extracted twice     with heptane (500 ml and 300 ml). The combined organic phases were     washed with satd. NaCl solution, dried over Na₂SO₄, and     concentrated. The residue was taken up in heptane, washed with KOH     solution (2 M), dried over Na₂SO₄ and concentrated. Yield: 76.26 g,     80%. -   Stage 2. A solution of 2-methoxy-1,3,4-trimethylbenzene (85.18 g,     532 mmole) in DCM (500 ml) was cooled to 0° C. A solution of     chlorosulfonic acid (38.9 ml, 585 mmole) was added dropwise to the     solution and stirred overnight at RT. After completion of the     reaction the reaction mixture was concentrated. The residue was     taken up in heptane and vigorously stirred. The heptane was decanted     and concentrated. Yield: 14.3 g, 11%.

The still remaining solids were taken up in DCM. The organic phase was washed with water, dried over Na₂SO₄ and concentrated. A further fraction was obtained in a yield of 38.6 g, 29%.

-   Stage 3. 2-(methylamino)ethanol (5.57 ml, 69.0 mmole) was dissolved     in DCM (100 ml) and triethylamine (20.2 ml, 144 mmole) was added.     The solution was cooled to 0° C. and a solution of     4-methoxy-2,3,5-trimethylbenzene-1-sulfonyl chloride (14.3 g, 57.5     mmole) dissolved in DCM (100 ml) was added dropwise and stirred for     3 hours at RT. After completion of the reaction HCl (0.5 M, 130 ml)     was added, the phases were separated, washed with water, dried over     Na₂SO₄ and concentrated. The crude product was used without further     purification in the next stage. Yield: 15.69 g, 95%. -   Stage 4. Tetra-n-butylammonium chloride (5.06 g, 18.2 mmole) was     added to a solution of     N-(2-hydroxyethyl)-4-methoxy-N,2,3,5-tetramethylbenzenesulfonamide     (15.69 g, 54.6 mmole) in toluene (300 ml) and cooled to 0° C. NaOH     solution (35%, 300 ml) was first of all added, followed by the     dropwise addition of tert.-butyl bromoacetate (11.9 ml, 81.9 mmole).     The mixture was then stirred for 3.5 hours at RT, following which     the aqueous phase was separated and the organic phase was washed     with water (3×300 ml) until neutral. The organic phase was dried     with Na₂SO₄, concentrated by evaporation in vacuo, and the residue     was purified by column chromatography on silica gel (heptane/ethyl     acetate 4:1→2:1). Yield: 19.23 g, 88%. -   Stage 5. An NaOH solution (6 M, 200 ml, 1.2 mole) was added to an     ice-cooled solution of tert.-butyl     2-(2-(4-methoxy-N,2,3,5-tetramethylphenylsulfonamido)ethoxy)-acetate     (19.23 g, 47.89 mmole) in THF (100 ml) and methanol (100 ml) and     stirred overnight at RT. The reaction solution was then acidified     with HCl (6 M, 250 ml) and extracted with DCM. The organic phase was     washed with saturated NaCl solution, dried over Na₂SO₄ and     concentrated by evaporation. Yield: 16.58 g, 100%.

Preparation of 2-(2-(N-isobutyl-4-methoxy-2,3,6-trimethylphenylsulfonamido)ethoxy)acetic Acid S7

-   Stage 1. Triethylamine (42.4 ml, 302 mmole) was added to a solution     of ethanolamine (8.01 ml, 133 mmole) dissolved in DCM (200 ml). The     solution was cooled on an ice bath and     2,3,6-trimethyl-4-methoxybenzenesulfonyl chloride (30 g, 121 mmole)     dissolved in DCM (200 ml) was added dropwise. The reaction mixture     was stirred overnight at RT. HCl solution (1 M, 125 ml) was then     added, and the organic phase was separated, washed with water, dried     over Na₂SO₄ and concentrated by evaporation to dryness. The crude     product was used without further purification in the next stage. -   Stage 2. K₂CO₃ (11.11 g, 80.4 mmole) and 1-bromo-2-methylpropane     (43.7 ml, 402 mmole) were added in succession to a solution of     N-(2-hydroxyethyl)-4-methoxy-2,3,6-trimethylbenzenesulfonamide (11     g, max. 38.69 mmole) in acetonitrile (400 ml) and heated overnight     under reflux. Further 1-bromo-2-methylpropane (21.9 ml, 201 mmole)     was added and heating was continued overnight under reflux. After     cooling to RT, the reaction mixture was first of all filtered     through filter earth and the filtrate was then concentrated by     evaporation to dryness. The crude product was purified by column     chromatography (silica gel, heptane/ethyl acetate 2:1). Yield: 8.30     g, 63% over 2 stages. -   Stage 3. n-Bu₄NCl (2.33 g, 8.4 mmole) was added to a solution of     N-(2-hydroxyethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzenesulfonamide     (8.3 g, 25.19 mmole) in toluene (100 ml) and DCM (100 ml), cooled to     0° C., after which aqueous 35% NaOH (175 ml) was first of all added,     followed by the dropwise addition of tert.-butyl bromoacetate (5.51     ml, 37.8 mmole). The reaction solution was stirred for 3 hours at     RT. After completion of the reaction the phases were first of all     separated, then washed with water until neutral, dried with Na₂SO₄,     and the organic solvent was distilled off. The crude product was     purified by column chromatography (silica gel, heptane/ethyl acetate     4:1). Yield: 10.8 g, 97%. -   Stage 4. The tert.-butyl     2-(2-(N-isobutyl-4-methoxy-2,3,6-trimethylphenyl-sulfonamido)ethoxy)-acetate     (10.8 g, 24.3 mmole) was dissolved in a mixture of methanol (100     ml), THF (100 ml) and aqueous NaOH solution (6 M, 100 ml, 600 mmole)     and stirred for 1 hour at RT. After completion of the reaction the     solution was concentrated and HCl (6 M, 125 ml) was added at 0° C.     The aqueous phase was extracted with DCM (100 ml) and ethyl acetate     (150 ml). The combined organic phases were dried over Na₂SO₄ and     concentrated. Remaining impurities were removed by repeated     dissolution in diisopropyl ether and diethyl ether, followed by     evaporation. Yield: 9.36 g, 99%.

Preparation of 3-(naphthalene-2-sulfonamido)-3-phenylpropionic Acid S8

-   Stage 1. Thionyl chloride (19.1 g, 162 mmole) was added dropwise to     a solution, cooled to 0° C., of 3-amino-3-phenylpropionic acid (8.9     g, 54 mmole) in methanol (3 ml/mmole). The reaction mixture was then     heated for 12 hours under reflux (DC check). The solvent was     completely removed and the residue was dried in vacuo. The crude     product was used without further purification in the next stage. -   Stage 2. Triethylamine (9.7 g, 96 mmole) was added to a solution,     cooled to 0° C., of methyl 3-amino-3-phenylpropionate (5.73 g, 32     mmole) in DCM. Naphthalene-2-sulfonyl chloride (8.7 g, 38.4 mmole)     dissolved in DCM (50 ml) was added to this reaction solution. The     reaction mixture was stirred for 3 hours at RT (DC check). After     completion of the reaction the reaction mixture was diluted with     DCM, washed with water and satd. NaCl solution and dried over     Na₂SO₄. The solvent was removed and the crude product was purified     by column chromatography (silica gel, ethyl acetate/hexane 3:7). -   Stage 3. LiOH x H₂O (0.25 g, 18 mmole) was added at a reaction     temperature of 0° C. to a solution of methyl     3-(naphthalene-2-sulfonamido)-3-phenylpropionate (3.3 g, 9 mmole) in     a methanol/water mixture (3:1, 90 ml). The reaction mixture was     stirred for 16 hours at RT. The solvent was removed under reduced     pressure, and the residue was taken up in water and washed with DCM.     The aqueous phase was then carefully acidified with HCl (1 N) and     extracted with ethyl acetate. The organic phase was washed with     water and satd. NaCl solution and dried over Na₂SO₄. The product was     obtained in sufficient purity after removing the solvent.

Preparation of (R)-3-(Naphthalene-2-sulfonamido)-3-phenylpropanoic Acid S9

Procedure for Step-1:

To a solution of (R)-ethyl 3-amino-3-phenylpropanoate hydrochloride (5.04 g, 21.9 mmol) and naphthalene-2-sulfonyl chloride (4.97 g, 21.9 mmol) in CH₂Cl₂ (60 mL) was added a solution of Et₃N (7.65 mL, 54.9 mmol) in CH₂Cl₂ (60 mL) at 0° C. over a period of 45 min. The reaction mixture was stirred at room temperature for 42 h and then washed with aqueous 1 M HCl (300 mL). The organic layer was dried (Na₂SO₄) and evaporated to dryness, which gave 8.05 g (96%) of S9-1 as a light pink solid.

Procedure for Step-2:

To a solution of sulfonamide S9-1 (7.82 g, 20.39 mmol) in THF (100 mL) and MeOH (100 mL) was added aqueous 4 M NaOH (15.35 mL, 61.4 mmol) and the mixture was stirred at room temperature for 18 h. The reaction was not complete according to TLC. Therefore, more aqueous 4 M NaOH (6 mL, 24 mmol) was added. After stirring for another 6 h the organic solvents were evaporated and aqueous 1 M HCl (100 mL) was added at 0° C. The aqueous layer was then extracted with CH₂Cl₂ (100 mL); the organic layer was dried (Na₂SO₄) and evaporated to dryness to afford carboxylic acid S9 (6.97 g, 96%).

The following amine building blocks were used for the synthesis of the sulfonamide compounds according to the invention:

Amine building block Structure Name A1 

1-ethyl-1,2,3,4- tetrahydropyrrolo[1,2]a]pyrazine A2 

1-(4-methoxyphenyl)-1,2,3,4- tetrahydropyrrolo[1,2]a]pyrazine A3 

1-phenyl-1,2,3,4- tetrahydropyrrolo[1,2]a]pyrazine A4 

1-(3,4-difluorophenyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine A5 

1-(3,4-dimethylphenyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine A6 

1-(3-fluorophenyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine A7 

1-(thiophen-2-yl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine A8 

1-(3-(trifluoromethyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine A9 

1-(3-methoxyphenyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine A10

1-(2-fluoro-4-(trifluoromethyl)phenyl)- 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine A11

1-phenethyl-1,2,3,4-tetrahydropyrrolo[1,2- a]pyrazine A12

1-propyl-1,2,3,4-tetrahydropyrrolo[1,2- a]pyrazine A13

1-isopropyl-1,2,3,4-tetrahydropyrrolo[1,2- a]pyrazine A14

1-ethyl-6-methyl-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine A15

1-isopropyl-6-methyl-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine A16

1-tert-butyl-1,2,3,4-tetrahydropyrrolo[1,2- a]pyrazine A17

1-methyl-1,2,3,4-tetrahydropyrrolo[1,2- a]pyrazine A18

N,N-dimethyl-1-(1-phenyl-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazin-6- yl)methanamine A19

1-phenyl-6-(pyrrolodin-1-ylmethyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine A20

1-phenyl-6-(piperidin-1-ylmethyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine A21

4-((1-phenyl-1,2,3,4-tetrahydropyrrolo[1,2- a]pyrazin-6-yl)methyl)morpholine A22

1-(1-benzyl-1,2,3,4-tetrahydropyrrolo[1,2- a]pyrazin-6-yl)-N,N-dimethylmethanamine A23

N,N-dimethyl(1-phenethyl-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazin-6- yl)methanamine A24

1-(1-butyl-1,2,3,4-tetrahydropyrrolo[1,2- a]pyrazin-6-yl)-N,N-dimethylmethanamine A25

N,N-dimethyl(1-thiophen-2-yl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazin-6- yl)methanamine A26

1-(1-ethyl-1,2,3,4-tetrahydropyrrolo[1,2- a]pyrazin-6-yl)-N,N,-dimethylmethanamine A27

1-(pyridine-3-yl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine A28

1-(6-chloropyridin-3-yl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine A29

5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine A30

6-((4-methylpiperazin-1-yl)methyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine A31

4-((1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-6- yl)methyl)morpholine A32

6-(pyrrolidin-1-ylmethyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine A33

6-(3-(4-methylpiperazin-1-yl)propyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine A34

1-(4-tert-butylphenyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine A35

4-(2-(1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin- 6-yl)ethyl)morpholine A36

6-(2-(pyrrolidin-1-yl)ethyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine A37

6-(2-(4-methylpiperazin-1-yl)ethyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine A39

tert-Butyl 6-(pyridin-4-yl)-3,4- dihydropyrrolo[1,2-a]pyrazine-2(1H)- carboxylate A40

tert-Butyl 6-(pyridin-4-ylmethyl)-3,4- dihydropyrrolo[1,2-a]pyrazine-2(1H)- carboxylate A41

tert-Butyl 6-(2-(pyridin-4-yl)ethyl)-3,4- dihydropyrrolo[1,2-a]pyrazine-2(1H)- carboxylate A42

tert-Butyl 6-(pyridin-3-yl)-3,4- dihydropyrrolo[1,2-a]pyrazine-2(1H)- carboxylate A43

tert-Butyl 6-(pyridin-3-ylmethyl)-3,4- dihydropyrrolo[1,2-a]pyrazine-2(1H)- carboxylate A44

tert-Butyl 6-(2-(pyridin-3-yl)ethyl)-3,4- dihydropyrrolo[1,2-a]pyrazine-2(1H)- carboxylate A45

tert-Butyl 2-(pyridin-4-yl)-5,6- dihydroimidazo[1,2-a]pyrazine-7(8H)- carboxylate A46

tert-Butyl 2-(pyridin-4-ylmethyl)-5,6- dihydroimidazo[1,2-a]pyrazine-7(8H)- carboxylate A47

tert-Butyl 2-(2-(pyridin-4-yl)ethyl)-5,6- dihydroimidazo[1,2-a]pyrazine-7(8H)- carboxylate A48

3-(Piperidin-1-ylmethyl)-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine

Synthesis of the Amine Building Blocks A1-17, A27-28, A34

-   Stage 1. NaOH (9.4 g, 0.23 mole) and tetrabutylammonium hydrogen     sulfate (0.8 g, 2.36 mmole) were added to a solution of the     corresponding pyrrole (0.06 mmole) in acetonitrile (33 ml) and     stirred for 30 minutes at RT. After the addition of     2-chloroethylamine hydrochloride (8.2 g, 0.07 mole) the reaction     mixture was heated for 24 hours under reflux. After the reaction     mixture had cooled the insoluble inorganic residue was filtered off     and the solvent was removed under reduced pressure. The crude     product was distilled in vacuo (35°-37° C., 0.037 mbar)

¹H NMR (400 MHz, CDCl₃)δ ppm 2.95-3.15 (m, 1 H) 3.89-4.00 (m, 1 H) 6.12-6.21 (m, 1 H) 6.64-6.73 (m, 1 H)

-   Literature: Cuadro A. M., Matia M. P., Garcia J. L., Vaquero J. J.     and Alvarez-Builla J.: Synth. Commun., 1991, 21(4), 535-544. -   Stage 2, Method A. A solution of the 2-(1H-pyrrol-1-yl)ethanamine     (0.1 mole) and the corresponding aldehyde (0.1 mole) in acetic acid     (250 ml) was stirred for 48 hours at RT. After completion of the     reaction the solvent was removed on a rotary evaporator and the     residue was taken up in aqueous sodium carbonate solution (10%) and     extracted with DCM. The organic phase was then dried over MgSO₄ and     concentrated by evaporation in vacuo. Purification was carried out     by column chromatography on neutral Al₂O₃ or silica gel or by     washing with 2-propanol or by crystallising from ethanol or     2-propanol/n-hexane -   Literature: I. Jirkovski, R. Baudy, Synthesis 1981, 481-483 -   Stage 2, Method B. Acetic acid (0.3 ml) was added to a solution of     the 2-(1H-pyrrol-1-yl)ethanamine (0.05 mole) and the corresponding     aldehyde (0.05 mole) in ethanol (25 ml) and heated for 10 minutes     under reflux. The reaction mixture was then stirred for a further     hour at RT. The reaction mixture was concentrated by evaporation on     a rotary evaporator and taken up in ethyl acetate. The organic phase     was washed with NaHCO₃ solution, dried over MgSO₄ and concentrated     by evaporation. Purification was carried out if necessary by column     chromatography on neutral Al₂O₃ or silica gel. -   Stage 2, Method C. Benzotriazole (54.5 mmole) and a spatula tip     amount of p-toluenesulfonic acid were added to a solution of the     2-(1H-pyrrol-1-yl)ethanamine (54.5 mmole) and corresponding aldehyde     (54.5 mmole) in toluene (500 ml). The reaction mixture was heated     overnight on a Dean-Stark water separator. After completion of the     reaction first of all the solvent was removed on a rotary evaporator     and the residue was taken up in ethyl acetate. The organic phase was     washed firstly with 1 M NaOH and then with satd. NaCl solution. The     organic phase was dried over Na₂SO₄ and then concentrated by     evaporation to dryness. Purification was carried out if necessary by     column chromatography by neutral Al₂O₃ or silica gel.

Stationary No. R¹ Method phase Solvent A1 Ethyl —* — — A2 4-methoxyphenyl —* — — A3 Phenyl A Al₂O₃ Gradient hexane → hexane: ethyl acetate 8:2 A4 3,4-difluorophenyl B Al₂O₃ Gradient hexane → hexane: ethyl acetate 95:5 A5 3,4-dimethylphenyl B Al₂O₃ Gradient hexane → hexane: ethyl acetate 8:2 A6 3-fluorophenyl B —** — A7 2-thiophenyl B Al₂O₃ Hexane A8 3-(trifluoro-methyl)phenyl B —** — A9 3-methoxyphenyl B —** — A10 2-fluoro-4-(trifluoro- B Al₂O₃ Gradient hexane → methyl)phenyl hexane: ethyl acetate 9:1 A11 Phenethyl B —** — A12 n-propyl —* — — A13 Isopropyl —* — — A14 Ethyl —* — — A15 Isopropyl —* — — A16 t-butyl B Silica gel DCM: methanol 98:2 A17 Methyl B Silica gel DCM: methanol 9:1 A27 3-pyridyl C Al₂O₃ Gradient hexane → hexane: ethyl acetate 7:3 → ethyl acetate A28 6-chloropyridin-3-yl B Al₂O₃ Gradient hexane → hexane: ethyl acetate 8:2 A34 4-tert-butylphenyl A —*** — *The amine is commercially obtainable **The crude product was used without further purification ***The crude product was recrystallised in ethanol.

5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine A29

-   Stage 1. A mixture of 2-aminopyrazin (25 g, 262.9 mmole),     chloroacetaldehyde (50% in water, 50 ml, 394 mmole) and NaHCO₃ (33.1     g, 394 mmole) was heated for 2 days at 100° C. The reaction mixture     was then cooled to RT, satd. K₂CO₃ solution (100 ml) was added, and     the mixture was washed with DCM. The organic phase was dried over     Na₂SO₄ and then concentrated by evaporation to dryness. Purification     was carried out by column chromatography on silica gel     (DCM/methanol, 95:5+5% NH₄OH [35%]. -   Stage 2. The imidazo[1,2-a]pyrazine (7.2 g, 60.44 mmole) was     dissolved in 2-methoxyethanol (100 ml) and PtO₂ (1.2 g, 5.13 mmole)     was added. The reaction mixture was stirred overnight at RT in an     autoclave under a hydrogen atmosphere (4 bar). The autoclave was     then flushed with nitrogen, the reaction mixture was filtered     through filter earth, concentrated, and the solvent residues were     then extracted with toluene. Purification was carried out by column     chromatography on silica gel (DCM/7 N NH₃ in methanol, 95:5)

Synthesis of the Amine Building Blocks A18-26, A30-A32 Synthesis of the Aminals

-   Stage 1, Method A. The formaldehyde solution (37% in water, 119 ml,     1.6 mole) was placed in a reaction vessel, dimethylamine solution     (40% in water, 405 ml, 3.2 mole) was added, and the mixture was then     stirred overnight at RT. After completion of the reaction K₂CO₃ was     added to the reaction mixture until phase separation occurred. The     phases were separated and dried over K₂CO₃. The product was purified     by means of fractional distillation (b.p. 80-84° C.).

¹H NMR (300 MHz, CDCl₃) δ_(ppm) 2.23 (s, 12 H) 2.73 (s, 2 H).

-   Literature: M. Gaudry, Y. Jasor, B. T. Khac, Org. Synth. 59, 153-158 -   Stage 1, Method B. The formaldehyde solution (37% in water, 59.5 ml,     0.8 mole) was placed in a reaction vessel and the corresponding     amine (1.6 mole) was added. The mixture was then stirred overnight     at RT. The reaction mixture was worked up by adding water (100 ml)     and was extracted four times with 200 ml of ethyl acetate each time.     The combined organic phases were dried over MgSO₄ and concentrated.     The crude product could be used without further purification. -   Stage 2. A reaction flask was heated and the aminal (60 mmole) was     added and dissolved or suspended in diethyl ether (70 ml). Acetyl     chloride (72 mmole) dissolved in diethyl ether (20 ml) was added     dropwise while cooling with ice. The reaction mixture was then     stirred overnight at RT. The precipitate that had formed was     filtered off through a glass frit, quickly transferred to a     round-bottomed flask and dried under an oil pump vacuum. The crude     product was used without further purification. -   Literature: G. Kienast, L. F. Tietze, Angew. Chemie 1976, 88, 8,     261-262

Aminal preparation method (Stage NR²R³ Aminal name 1) Iminium salt name NMe₂ N,N,N′,N′- A N-methyl-N- tetramethylmethanediamine methylenemethaniminium chloride

Dipyrrolidin-1-ylmethane B 1-methylene-pyrrolidinium chloride

Dimorpholinomethane B 1-methylene-morpholinium chloride

Dipiperidin-1-ylmethane B 1-methylene-piperidinium chloride

Bis-(4-methylpiperazin-1- yl)methane B 4-methyl-1-methylene- piperazin-1-ium chloride

1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine

TFA (0.5 ml) was added to a solution of 1-(2-aminoethyl)pyrrole (9 mmole) in ethanol (20 ml) and 37% formaldehyde (9 mmole). The reaction mixture was stirred for 15 minutes at 50° C. The reaction solution was then cooled to 25° C. and stirred for 4 hours at this temperature. The reaction solution was concentrated by evaporation under reduced pressure. The residue was taken up in ethyl acetate and washed with aqueous sodium carbonate solution. The organic phase was separated, dried over Na₂SO₄ and concentrated by evaporation to dryness. The product was used without further purification.

Aminoalkylation

-   Stage 1, Method A. The corresponding 1-substituted     1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine (1 equiv.) was dissolved in     2.5 ml/mmole DCM in a heated three-necked flask. Di-tert-butyl     dicarbonate (0.5 equiv.) was dissolved in 1.5 ml/mmole DCM and added     dropwise within 30 minutes. The suspension was stirred overnight at     RT. The reaction mixture was worked up by adding satd. sodium     carbonate solution and the organic phase was separated. The aqueous     phase was then extracted twice with DCM. The organic phases were     combined, dried over magnesium sulfate and concentrated by     evaporation. The products were purified by column chromatography on     silica gel. -   Stage 1, Method B. Diisopropylethylamine (12.15 mmole) and     di-tert-butyl dicarbonate (8.9 mmole) were added to a solution of     the correspondingly 1-substituted     1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine (8.1 mmole) in DCM. The     reaction mixture was stirred for 16 hours at 25° C. The organic     phase was then washed with sodium carbonate solution, water and     satd. NaCl solution, dried over Na₂SO₄ and concentrated by     evaporation. The crude product was purified by column chromatography     (silica gel, ethyl acetate/DCM, 99:1)

R¹ Method Name Ethyl A tert-butyl 1-ethyl-3,4- dihydropyrrolo[1,2-]]pyrazine- 2(1H)-carboxylate Butyl A tert-butyl 1-butyl-3,4- dihydropyrrolo[1,2-a]pyrazine- 2(1H)-carboxylate Phenyl A tert-butyl-1-phenyl-3,4-dihydropyrrolo[1,2- a]pyrazine-2(1H)-carboxylate Benzyl A tert-butyl-1-benzyl-3,4-dihydropyrrolo[1,2- a]pyrazine-2(1H)-carboxylate Phenethyl A tert-butyl 1-phenethyl-3,4-dihydroppyrrolo[1,2- a]pyrazine-2(1H)-carboxylate 2-thiophenyl A tert-butyl-1-(thiophen-2-yl)- 3,4-dihydroppyrrolo[1,2- a]pyrazine-2(1H)-carboxylate H B tert-butyl 3,4- dihydroppyrrolo[1,2-a]pyrazine-2(1H)- carboxylate Stage 2. Methods for the Aminoalkylation

-   Method A. The BOC-protected 1-substituted     1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine (1 equiv.) was dissolved in     acetonitrile (5 ml/mmole), the corresponding iminium salt (1 equiv.)     was added and the reaction mixture was stirred overnight at RT. For     the working-up the reaction mixture was first adjusted to pH 1 with     1N HCl and then extracted three times with diethyl ether. The     aqueous phase was then made alkaline with sodium hydrogen carbonate     solution and extracted three times with diethyl ether. The combined     organic phases were dried over magnesium sulfate and concentrated by     evaporation on a rotary evaporator. The crude product was purified     if necessary by column chromatography on silica gel (solvent:     gradient: DCM/methanol 99:1→95:5). -   Method B. The BOC-protected 1-substituted     1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine (1 equiv.) was dissolved in     acetonitrile (10 ml/mmole), the corresponding iminium salt (1     equiv.) was added, and the reaction mixture was stirred overnight at     RT. For the working-up the reaction mixture was diluted with ethyl     acetate and then washed with sodium hydrogen carbonate solution,     water and satd. NaCl solution, dried over Na₂SO₄ and concentrated by     evaporation. The crude product was purified by column chromatography     (silica gel, DCM/methanol 95:5)     Stage 3: Methods for Cleavage of the Protective Groups -   Method A. The aminoalkylated Boc-protected 1-substituted     1,2,3,4-tetrahydropyrrolo-[1,2-a]pyrazine was dissolved in DCM (7     ml/mmole), TFA (10 equiv.) was added, and the reaction mixture was     stirred overnight at RT. After completion of the reaction (DC check)     the reaction mixture was made alkaline with sodium carbonate     solution. The phases were separated and the aqueous phase was     extracted three times with DCM. The combined organic phases were     dried over magnesium sulfate and the solvent was removed on a rotary     evaporator. The crude product could be used without further     purification. -   Method B. The aminoalkylated Boc-protected 1-substituted     1,2,3,4-tetrahydropyrrolo-[1,2-a]pyrazine was dissolved in ethyl     acetate (1 ml/mmole) and a satd. solution of HCl in ethyl acetate (3     ml/mmole) was added at 0° C. The reaction mixture was then heated to     RT and stirred for 2 hours. The solvent was removed and the product     was used without further purification.

Method for Amino- removal of alkylation protective method groups No. R¹ NR²R³ (Stage 2) (Stage 3) Name A18 Phenyl NMe₂ A A N,N-dimethyl-1-(1-phenyl-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazin-6- yl)methanamine A19 Phenyl

A A 1-phenyl-6-(pyrrolidin-1-ylmethyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine A20 Phenyl

A A 1-phenyl-6-(piperidin-1-ylmethyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine A21 Phenyl

A A 4-((1-phenyl-1,2,3,4-tetrahydropyrrolo[1,2- a]pyrazin-6-yl)methyl)morpholine A22 Benzyl NMe₂ A A 1-(1-benzyl-1,2,3,4-tetrahydropyrrolo[1,2- a]pyrazin-6-yl)-N,N-dimethylmethanamine A23 Phenethyl NMe₂ A A N,N-dimethyl-1-(1-phenethyl-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazin-6- yl)methanamine A24 Butyl NMe₂ A A 1-(1-butyl-1,2,3,4-tetrahydropyrrolo[1,2- a]pyrazin-6-yl)-N,N-dimethylmethanamine A25 2-thienyl NMe₂ A A N,N-dimethyl-1(1-(thiophen-2-yl)-1,2,3,4- tetrahydro-pyrrolo[1,2-a]pyrazin-6- yl)methanamine A26 Ethyl NMe₂ A A 1-(1-ethyl-1,2,3,4-tetrahydropyrrolo[1,2- a]pyrazin-y-yl)-N,N-dimethylmethanamine A30 H

B B 6-((4-methylpiperazin-1-yl)methyl-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine A31 H

B B 4-((1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin- 6-yl)methyl)morpholine A32 H

B B 6-(pyrrolidin-1-ylmethyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine

Preparation of the Amine Building Blocks A33

-   Stage 1. A solution of oxalyl chloride (1 equiv.) in DCE (15 ml) was     added to an ice-cooled solution of dry DCE (15 ml) and dry DMF (1     equiv.) and stirred for 15 minutes at RT. The solution was re-cooled     to 0° C. and a solution of tert-butyl     3,4-dihydropyrrolo-[1,2-]pyrazine-2(1H)-carboxylate (5 g, 22.25     mmole) in DCE (15 ml) was added. The reaction solution was stirred     for 30 minutes at this temperature (DC check). Ice was then added,     followed by aqueous NaOH solution (50%). The aqueous phase was     extracted with DCM and the organic phase was then washed in     succession with water and satd. NaCl solution. After drying over     Na₂SO₄, the solvent was removed in a rotary evaporator. The     resulting crude product was used without further purification in the     next stage. -   Stage 2. A solution of triethylphosphonium acetate (48.9 mmole) in     dry THF (160 ml) was slowly added to a suspension of NaH (60%, 48.9     mmole) in dry THF (160 ml), cooled to 0° C., and then stirred for 60     minutes at 25° C. The reaction mixture was then cooled to 0° C. and     the aldehyde (from Stage 1, 22.25 mmole) in dry THF (160 ml) was     added dropwise, the temperature being maintained constant. The     reaction mixture was then heated to 25° C. and stirred for 16 hours     at this temperature until the reaction had gone to completion. The     reaction mixture was hydrolysed first with ice and then with satd.     NaCl solution. The aqueous phase was extracted with ethyl acetate.     The organic phase was then washed with water and satd. NaCl     solution. The organic phase was dried over Na₂SO₄ and the solvent     was removed on a rotary evaporator. The crude product was purified     by column chromatography on silica gel (solvent: DCM/ethyl acetate,     95:5). -   Stage 3. A solution of the ester (from Stage 2, 9.37 mmole) in     methanol (150 ml) was firstly deoxygenated with argon over a period     of 15 minutes and Pd/C (10%, 20 wt. %) was added. The reaction     mixture was hydrogenolysed for 45 minutes under atmospheric pressure     (LCMS check). After completion of the reaction the reaction mixture     was filtered through filter earth and washed with methanol. The     combined organic phases were concentrated and the resulting product     was used without further purification in the next stage. -   Stage 4. DIBAL-H (1 equiv., 1.5 M in toluene) was added dropwise at     −70° C. and under an argon atmosphere to a solution of the     tert-butyl     6-(2-ethoxycarbonylethyl)-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carbonate     (from Stage 3, 1 equiv.) in dry toluene (7 ml/mmole). The reaction     mixture was stirred for 1 hour at this temperature, after which the     educt had completely reacted (DC check). Methanol (30 ml) was added     at −70° C. and the reaction mixture was heated to 25° C. Saturated     NaCl solution (30 ml) was added. The reaction mixture was stirred     for 30 minutes at this temperature and then filtered through filter     earth. The reaction mixture was washed several times with ethyl     acetate. The combined organic phases were washed with saturated NaCl     solution and then dried over Na₂SO₄, and the solvent was removed on     a rotary evaporator. The product obtained was used without further     purification in the next stage. -   Stage 5. The corresponding amine (1 equiv.) and glacial acetic acid     (170 μl/mmole) were added to a solution of the aldehyde (from Stage     4, 1.5 equiv.) in DCM (20 ml/mmole) at 25° C. and stirred for 30     minutes at this temperature. Sodium triacetoxy boron hydride (4     equiv.) was added to the reaction mixture and stirred for 20 hours     at 25° C. (DC check). The reaction mixture was then diluted with DCM     and washed with saturated, aqueous sodium hydrogen carbonate     solution. The reaction mixture was dried over Na₂SO₄ and the solvent     was removed on a rotary evaporator. The crude product was purified     by column chromatography on silica gel (solvent: DCM/methanol, 9:1).

Preparation of the Amine Building Blocks A35 and A36

The synthesis of the aldehyde reacted in Stage 1 was carried out according to Stage 1 of the synthesis of the amine building block A33.

-   Stage 1. Ammonium acetate (0.45 equiv.) was added to a solution of     the aldehyde (10.4 mmole) in nitromethane (14.5 ml). The reaction     mixture was then heated under reflux for 2 hours (DC check). After     completion of the reaction the nitromethane was carefully removed     under reduced pressure. The residue was taken up in ethyl acetate     and washed successively with water and saturated sodium chloride     solution. The organic phase was dried over sodium sulfate and the     solvent was removed on a rotary evaporator. The crude product was     purified by column chromatography on silica gel (solvent:     hexane/ethyl acetate 9:1). -   Stage 2. The nitro compound from Stage 1 (32 mmole) was added to a     mixture of methanol and DMF (2:1, 17.5 ml/mmole) and cooled to 0° C.     NaBH₄ (48 mmole) was added in portions to this mixture. The reaction     mixture was stirred for 30 minutes at 0° C. (DC check). Water (14     ml/mmole) and 1 drop of acetic acid were then added. The product was     extracted with DCM. The organic phase was washed with saturated     sodium chloride solution, dried over sodium sulfate, and the solvent     was removed on a rotary evaporator. The crude product was purified     by column chromatography on silica gel (solvent: hexane/ethyl     acetate 9:1). -   Stage 3. A solution of the nitro compound (3.5 g, 12 mmole) from     Stage 2 in ethanol (60 ml) was cooled to 0° C. and zinc dust (10     equiv.) was added in portions. The reaction mixture was stirred at     0° C. for 12 hours and then filtered through celite. The filtrate     was washed several times with ethanol. The combined organic phases     were concentrated by evaporation. The brown residue was taken up in     DCM and washed in succession with sodium carbonate solution and     saturated sodium chloride solution. The residue was then dried over     sodium sulfate and the solvent was removed on a rotary evaporator.     The crude product was used without further purification. -   Stage 4. The     tert-butyl-6-(2-aminoethyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate     (1 equiv.) was dissolved in toluene (5 ml/mmole) and potassium     carbonate (5 equiv.) was added. 1-chloro-2-(2-chloroethoxy)ethane or     2-chloro-N-(2-chloroethyl)-N-methyl-methanamine (1.5 equiv.) was     then added at RT. The reaction mixture was heated for 16 hours at     100° C. in a closed tube (DC check). After completion of the     reaction the mixture was cooled to RT, diluted with ethyl acetate,     and washed in succession with water and saturated sodium chloride     solution. The organic phase was dried over sodium sulfate and the     solvent was removed on a rotary evaporator. The crude product was     purified by column chromatography on silica gel (solvent:     DCM/methanol, NRR′=morpholine: 98:2, NRR′=methylpiperazine: 94:6).

Preparation of the Amine Building Block A37

-   Stage 1. Butanediol (5 g, 56 mmole) was dissolved in DCM,     triethylamine (280 mmole) was added and the mixture was cooled to     0° C. Methanesulfonic acid chloride (140 mmole) was added at this     temperature and stirred for 1 hour at 0° C. After completion of the     reaction the mixture was diluted with DCM and washed in succession     with water and saturated sodium chloride solution. The organic phase     was dried over sodium sulfate and the solvent was removed on a     rotary evaporator. The crude product was used without further     purification. -   Stage 2. The     tert-butyl-6-(2-aminoethyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate     (1 equiv.) was dissolved in toluene (5 ml/mmole) and potassium     carbonate (5 equiv.) was added. Butane-1,4-diyldimethanesulfonate     (1.5 equiv.) was then added at RT. The reaction mixture was heated     for 16 hours at 100° C. in a closed tube (DC check). After     completion of the reaction the mixture was cooled to RT, diluted     with ethyl acetate, and washed in succession with water and     saturated sodium chloride solution. The organic phase was dried over     sodium sulfate and the solvent was removed on a rotary evaporator.     The crude product was purified by column chromatography on silica     gel (solvent: DCM/methanol).

Preparation of the Amine Building Block A39 tert-Butyl 6-(pyridin-4-yl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

Procedure for Step-1:

To a solution containing 4 g (0.06 mol) of pyrrole in 33 ml of acetonitrile were added 9.4 g (0.23 mol) of powdered sodium hydroxide and 0.8 g (2.36 mmol) of tetrabutylammonium hydrogensulfate. After the mixture was stirred at 25° C. for 30 minutes, 2-chloroethylamine hydrochloride (8.2 g, 0.07 mol) was added. The reaction mixture was refluxed for 24 hrs, inorganic solid was filtered off and the solvent was removed under reduced pressure to get crude 1-(2-aminoethyl)pyrrole. This was distilled under vacuum to get a colorless liquid that was used in the next step directly. Yield: 30% (crude)

Procedure for Step-2:

To a ethanol solution (20 ml) of 1-(2-aminoethyl)pyrrole (9 mmol) and 37% formaldehyde (9 mmol) was added TFA (0.5 ml) and the resulting reaction mixture was allowed to stir at 50° C. for 15 minutes. It was then cooled to come to 25° C. and stirred at this temperature for 4 hrs. Solvent was removed under reduced pressure, residue was dissolved in ethyl acetate, basified with aqueous sodium carbonate solution, organic layer was separated and dried over sodium sulfate. Evaporation of the organic layer gave the crude 1,2,3,4-Tetrahydro-pyrrolo[1,2-a]pyrazine which was dissolved in dichloromethane (90 ml) at to it DIPEA (12.15 mmol) and boc anhydride (8.9 mmol) were added at 0° C. The resulting reaction mixture was allowed to stir for 16 hrs at 25° C. Organic layer was washed with sodium carbonate, water and brine and finally dried over sodium sulfate. Evaporation of the organic layer gave the crude product which was purified by column chromatography (1% ethyl acetate in dichloromethane) or (10% ethyl acetate in hexane).

Procedure for Step-3:

To a solution of 3,4-Dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (200 mg, 0.9 mmol) obtained from step-2 in dry dimethyl acetamide (200 μL) was added cesium acetate (3 eqv), diisopropyl amine (4 eqv) and 4-bromopyridine hydrochloride (2 eqv) under argon atmosphere. To this reaction mixture was then added Pd(OAc)₂ (0.15 eqv) under inert atmosphere and the reaction was heated at 130° C. for 16 hrs. It was then diluted with ethyl acetate, filtered through celite bed and the organic layer was washed successively with water and brine. Evaporation of organic layer under reduced pressure gave the crude product which was purified by column chromatography. Yield: 40%

Preparation of the Amine Building Block A40 tert-Butyl 6-(pyridin-4-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

Procedure for Step-1:

Compound A (3 g, 13.5 mmol) was taken in dry toluene (30 ml) and to it was added zinc dust (3 eqv) under inert atmosphere. The resulting reaction mixture was stirred at 25° C. for 5 minutes and then isonicotinoyl chloride hydrochloride (1.5 eqv) was added under stirring. Stirring was continued for further 16 hrs. Reaction mixture was filtered through celite bed, diluted with ethyl acetate, organic layer was washed successively with water and brine and finally dried over sodium sulfate. Evaporation of organic layer under reduced pressure gave the crude product that was purified by column chromatography (5% methanol in dichloromethane) Yield: 40%

Procedure for Step-2:

A 2:1 mixture of AcOH-MeOH (36 ml) was added to the keto compound (3.6 mmol) and to it zinc dust (50 eqv) was added under stirring. The resulting reaction mixture was allowed to stir at 25° C. for 16 hrs (monitored by LCMS) and filtered through celite bed. Solvent was completely evaporated, residue was taken in ethyl acetate, organic layer was washed successively with sodium bicarbonate and brine and finally dried over sodium sulfate. Evaporation of organic layer under reduced pressure gave the crude product which was purified by column chromatography (5% methanol in dichloromethane). Yield: 26%

Preparation of the amine building block A41 tert-Butyl 6-(2-(pyridin-4-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

Procedure for Step-1:

To an ice cold solution of dry DCE (15 ml) and dry DMF (1 eqv) was added a solution of oxalyl chloride (1 eqv) in dry DCE (15 ml) and the resulting reaction mixture was stirred at 25° C. for 15 minutes. Reaction was again cooled to 0° C. and to it was added a solution of 3,4-Dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (5 gm, 22.25 mmol) in dry DCE (15 ml) and the reaction was stirred at the same temperature for 30 minutes (monitored by TLC). It was quenched with ice, 50% aqueous NaOH solution was then added, aqueous layer was extracted with DCM and the organic layer was washed successively with water and brine. After drying over sodium sulfate, organic layer was evaporated under reduced pressure to get the crude product which was used immediately in the next step without any further purification. Yield: 60% (crude)

Procedure for Step-2:

To a solution of 4-picoline (4 mmol) in dry THF (10 ml) was added n-BuLi (1.57M, 2.5 ml, 4 mmol) at −78° C. and the resulting reaction mixture was allowed to stir at 25° C. for 1 hr. It was again cooled to 0° C. and the aldehyde obtained from step-1 (1 g, 4 mmol) was added to the reaction mixture drop wise. After stirring at 25° C. for 3 hrs, reaction mixture was quenched with water (5 ml), extracted with ethyl acetate and the combined organic layer was washed with brine. After drying over sodium sulfate, organic layer was evaporated under reduced pressure to get the crude alcohol that was purified by column chromatography (2% methanol in dichloromethane). Yield: 48%

Procedure for Step-3:

To a solution of the alcohol obtained from step-2 (1 g, 2.91 mmol) in xylene (15 ml) wadded p-toluene sulfonic acid (0.05 eqv) and the resulting reaction mixture was refluxed using a dean-stark apparatus for 5 hrs (monitored by TLC). Reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed successively with saturated sodium bicarbonate solution, water and brine. Organic layer was dried over sodium sulfate evaporated under reduced pressure to get the crude product that was purified by column chromatography (2% methanol in dichloromethane). Yield: 56%

Procedure for Step-4:

A solution of the compound obtained from step-3 was taken in methanol (15 ml) and deoxygenated with argon. To it was added 10% Pd—C (150 mg) and the resulting reaction mixture was hydrogenated under atmospheric pressure for 3 hrs. It was filtered through celite bed, residue washed with methanol and the combined organic layer was evaporated to dryness to get the crude product which was used directly in the next step without any further purification. Yield: 80% (crude)

Preparation of the Amine Building Block A42 tert-Butyl 6-(pyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

Procedure:

To a solution of 3,4-Dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (2 g, 9 mmol) in dry dimethyl acetamide (2 ml) was added cesium acetate (3 eqv), diisopropyl amine (4 eqv) and 3-bromopyridine (2 eqv) under argon atmosphere. To this reaction mixture was then added Pd(OAc)₂ (0.15 eqv) under inert atmosphere and the reaction was heated at 130° C. for 16 hrs. It was then diluted with ethyl acetate, filtered through celite bed and the organic layer was washed successively with water and brine. Evaporation of organic layer under reduced pressure gave the crude product that was purified by column chromatography. Yield: 40%

Preparation of the Amine Building Block A43 tert-Butyl 6-(pyridin-3-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

Procedure for Step-1: Same as step-1 of A41 Procedure for Step-2:

To a solution of n-BuLi (1.57 M, 2.54 ml, 4 mmol) in dry ether (5 ml) at −78° C. was added 3-bromo pyridine (4 mmol) and the reaction mixture was allowed to stir at the same temperature for 30 minutes. To it aldehyde (4 mmol) obtained from step-1 in dry ether (10 ml) was added drop wise and the resulting reaction mixture was allowed to stir at 25° C. for 16 hrs (monitored by TLC). Reaction was quenched with water, extracted with ethyl acetate, combined organic layer was washed with brine and finally dried over sodium sulfate. Evaporation of organic layer under reduced pressure gave the crude product which was purified by column chromatography (3% methanol in dichlormethane). Yield: 30%

Procedure for Step-3:

A 2:1 mixture of AcOH-MeOH (16 ml) was added to the keto compound (3.6 mmol) and to it zinc dust (50 eqv) was added under stirring. The resulting reaction mixture was allowed to stir at 25° C. for 16 hrs (monitored by LCMS) and filtered through celite bed. Solvent was completely evaporated, residue was taken in ethyl acetate, organic layer was washed successively with sodium bicarbonate and brine and finally dried over sodium sulfate. Evaporation of organic layer under reduced pressure gave the crude product that was purified by column chromatography (5% methanol in dichloromethane). Yield: 35%

Preparation of the Amine Building Block A44 tert-Butyl 6-(2-(pyridin-3-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

Procedure for Step-1: Same as step-1 of A41 Procedure for Step-2:

To an ice cold suspension of the wittig salt (4 mmol) in dry THF (25 ml) was slowly added n-BuLi (5 mmol) and the resulting reaction mixture was allowed to stir at that temperature for 30 minutes. To it aldehyde B (2 mmol) in dry THF (10 ml) was added at 0° C. and allowed to stir for further 1 hr. Reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. Organic layer was washed with water and brine and finally dried over sodium sulfate. Evaporation of organic layer under reduced pressure gave the crude product that was unstable and used immediately without any further purification.

Procedure for Step-3:

To a DMA solution (2 ml) of the crude compound obtained from step-2 (9.12 mmol) was added cesium acetate (3 eqv), diisopropyl amine (4 eqv) and 3-bromopyridine (2 eqv) under argon atmosphere. To this reaction mixture was then added Pd(OAc)₂ (0.15 eqv) under inert atmosphere and the reaction was heated at 130° C. for 16 hrs. It was then diluted with ethyl acetate, filtered through celite bed and the organic layer was washed successively with water and brine. Evaporation of organic layer under reduced pressure gave the crude product that was purified by column chromatography (5% methanol in dichloromethane). Yield: 15%

Procedure for Step-4:

A solution of the compound obtained from step-3 (400 mg) was taken in methanol (10 ml) and deoxygenated with argon. To it was added 10% Pd—C (200 mg) and the resulting reaction mixture was hydrogenated under atmospheric pressure for 3 hrs. It was filtered through celite bed, residue washed with methanol and the combined organic layer was evaporated to dryness to get the crude product which was used directly in the next step without any further purification. Yield: 80% (crude)

Preparation of the Amine Building Block A45 tert-Butyl 2-(pyridin-4-yl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate

Procedure for Step-1:

To a solution of 2-aminopyrazine (1.87 g) in dry acetone (30 ml) was added potassium carbonate (3 eqv), 4-bromoacetyl pyridine (2 eqv) and the resulting reaction mixture was heated at 60° C. for 20 hrs. Reaction mixture was filtered through a celite bed, residue washed with DCM and combined organic layer was evaporated completely to get a brown residue. It was again dissolved in ethyl acetate, washed with water and brine and finally dried over sodium sulfate. Evaporation of organic layer gave the crude product which was purified by column chromatography (1% methanol in dichloromethane). Yield: 12%, 30% Starting material recovered.

Procedure for Step-2:

To a dry dioxane solution (22 ml) of the compound obtained from step-1 (2.55 mmol) was added lithium borohydride (2 eqv) portion wise at 25° C. and the resulting reaction mixture was stirred at this temperature for 10 minutes. It was then warmed to 60° C. and kept at that temperature for 30 minutes (monitored by TLC). Reaction was cooled to 0° C. and acidified with 1(N)HCl. Dioaxane was completely evaporated, dichloromethane (5 ml), diisopropyl ethyl amine (2.5 eqv) and boc-anhydride (1.5 eqv) was added to the residue and the resulting reaction mixture was allowed to stir at 25° C. for 16 hrs. It was diluted with dichloromethane, organic layer was washed with water and brine and finally dried over sodium sulfate. Evaporation of the organic layer gave the crude product which was purified by column chromatography (5% methanol in dichloromethane). Yield: 58%

Preparation of the Amine Building Block A46 tert-Butyl 2-(pyridin-4-ylmethyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate

Procedure for Step-1:

To a THF solution (40 ml) of Diisopropyl amine (4.46 ml, 1.5 eqv) was added BuLi (1.88 M, 1.5 eqv) at −15° C. and the resulting reaction mixture was allowed to stir at same temperature for 20 minutes. It was then cooled to −78° C. and 2-chloro-3-iodopyridine (5 g, 20.92 mmol) in THF (10 ml) was added dropwise at the same temperature and allowed to stir for 1 hr at −78° C. Reaction was quenched with water (10 ml), stirred at ambient temperature for 15 minutes and extracted with ethyl acetate. Organic layer was washed successively with brine and finally dried over sodium sulfate. Evaporation of organic layer under reduced pressure gave the crude product which was immediately used in the next step without any further purification. Yield: 80% (Crude)

Procedure for Step-2:

To a solution of 2-amino pyrazine (20 g, 210 mmol) in dimethoxy ethane (400 ml) was added ethyl bromopyruvate (32.8 ml) at 25° C. and the resulting reaction mixture was allowed to stir at the same temperature for 4 hrs. It was then cooled to 0° C. and stirred for 30 minutes. The separated solid was filtered and washed with ether. Solid residue was taken in ethanol (1000 ml) and refluxed for 4 hrs. Solvent was removed completely, residue taken in chloroform (1000 ml), saturated sodium bicarbonate solution (700 ml) was added to it and the mixture was allowed to stir for 45 minutes. The mixture was filtered through celite bed, washed several times with chloroform and filtrate was dried over sodium sulfate. Evaporation of the organic layer under reduced pressure gave the crude mass, which was purified by crystallization using ether-methanol mixture. Yield: 20%

Procedure for Step-3:

To a well stirred suspension of the ester obtained from step-1 (10 g, 52.3 mmol) in dioxane (400 ml) was added lithium borohydride (2 eqv) at 25° C. and the resulting reaction mixture was allowed to stir at the same temperature for 10 minutes. It was then warmed to 60° C. and kept at this temperature for 20 minutes (! Higher temperature and more reaction time reduce the yield and quality of reaction). Reaction mixture was then cooled to 0° C., acidified with 1N HCl and dioxane was completely evaporated under reduced pressure. Residue was taken in dichloromethane (200 ml), TEA (4eqv) and Boc-anhydride (1.2 eqv) was added to it and the resulting reaction mixture was allowed to stir at 25° C. for 16 hrs. Organic layer was washed with water and brine and finally dried over sodium sulfate. Evaporation of organic layer gave the crude product which was purified by column chromatography (70% ethyl acetate in hexane). Yield: 27%

Procedure for Step-4:

To a solution of the boc-ester (1 g, 3.38 mmol) obtained from step-3 in dry toluene (40 ml) was added DIBAL (1M, 3.7 mmol) at −78° C. and the reaction mixture was allowed to stir at this temperature for 5 hrs (monitored by TLC). Reaction was quenched with methanol (3.7 ml) and was slowly brought to 25° C. Brine (10 ml) was added to it and filtered through celite bed. Residue was washed with dichloromethane and combined organic layer was evaporated to get the crude aldehyde, which was used directly in the next step without any further purification. Yield: 800 mg (crude)

Procedure for Step-5:

To a ether solution (17 ml) of 2-chloro-4-iodo pyridine (1 eqv) was added BuLi (1.2 eqv) at −78° C. and the resulting reaction mixture was allowed to stir at the same temperature for 1 hr. To it was added the aldehyde (1 eqv) obtained from step-4 at −78° C. and stirred for 1 hr at the same temperature. It was quenched with water, extracted with ethyl acetate and the organic layer was washed successively with brine and finally dried over sodium sulfate. Evaporation of organic layer under reduced pressure gave the crude product which was purified by column chromatography. Yield: 35%

Procedure for Step-6:

A solution of the compound obtained from step-5 was taken in methanol (10 ml/mmol) and deoxygenated with argon. To it was added 10% Pd—C (50% by wt of the alcohol) and the resulting reaction mixture was hydrogenated under atmospheric pressure for 16 hrs. It was then filtered through celite bed, residue washed with methanol and the combined organic layer was evaporated to dryness to get the crude product which was used directly in the next step without any further purification. Yield: 44% (crude)

Procedure for Step-7:

To a solution of the alcohol (1 eqv) obtained from step-6 in methanol (5 ml/mmol) was added glacial acetic acid (10 ml/mmol), Zn dust (50 eqv) and the resulting reaction mixture was allowed to stir at ambient temperature for 16 hrs. Reaction mixture was filtered through celite bed, washed with methanol and combined organic layer was evaporated completely. It was then taken in ethyl acetate, washed with sodium bicarbonate, water and brine and finally dried over sodium sulfate. Evaporation of organic layer under reduced pressure gave the crude product which was purified by column chromatography (2% methanol in dichloromethane). Yield: 26%

Preparation of the Amine Building Block A47 tert-Butyl 2-(2-(pyridin-4-yl)ethyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate

Procedure for Step-1:

To a solution of 2-amino pyrazine (20 g, 210 mmol) in dimethoxy ethane (400 ml) was added ethyl bromopyruvate (32.8 ml) at 25° C. and the resulting reaction mixture was allowed to stir at the same temperature for 4 hrs. It was then cooled to 0° C. and stirred for 30 minutes. The separated solid was filtered and washed with ether. Solid residue was taken in ethanol (1000 ml) and refluxed for 4 hrs. Solvent was removed completely, residue taken in chloroform (1000 ml), saturated sodium bicarbonate solution (700 ml) was added to it and the mixture was allowed to stir for 45 minutes. The mixture was filtered through celite bed, washed several times with chloroform and filtrate was dried over sodium sulfate. Evaporation of the organic layer under reduced pressure gave the crude mass, which was purified by crystallization using ether-methanol mixture. Yield: 20%

Procedure for Step-2:

To a well stirred suspension of the ester obtained from step-1 (10 g, 52.3 mmol) in dioxane (400 ml) was added lithium borohydride (2 eqv) at 25° C. and the resulting reaction mixture was allowed to stir at the same temperature for 10 minutes. It was then warmed to 60° C. and kept at this temperature for 20 minutes (! Higher temperature and more reaction time reduce the yield and quality of reaction). Reaction mixture was then cooled to 0° C., acidified with 1N HCl and dioxane was completely evaporated under reduced pressure. Residue was taken in dichloromethane (200 ml), TEA (4eqv) and Boc-anhydride (1.2 eqv) was added to it and the resulting reaction mixture was allowed to stir at 25° C. for 16 hrs. Organic layer was washed with water and brine and finally dried over sodium sulfate. Evaporation of organic layer gave the crude product which was purified by column chromatography (70% ethyl acetate in hexane). Yield: 27%

Procedure for Step-3:

To a solution of the boc-ester (1 g, 3.38 mmol) obtained from step-2 in dry DCM (40 ml) was added DIBAL (1M, 3.7 mmol) at −78° C. and the reaction mixture was allowed to stir at this temperature for 5 hrs (monitored by TLC). Reaction was quenched with methanol (3.7 ml) and was slowly brought to 25° C. Brine (10 ml) was added to it and filtered through celite bed. Residue was washed with dichloromethane and combined organic layer was evaporated to get the crude aldehyde, which was used directly in the next step without any further purification. Yield: 800 mg (crude)

Procedure for Step-4:

To a solution of 4-picoline (3 mmol) in dry THF (10 ml) was added n-BuLi (1.57M, 3 mmol) at −78° C. and the resulting reaction mixture was allowed to stir at 25° C. for 1 hr. It was again cooled to 0° C. and the aldehyde obtained from step-3 (3 mmol) was added to the reaction mixture drop wise. After stirring at 25° C., reaction mixture was quenched with water (5 ml), extracted with ethyl acetate and the combined organic layer was washed with brine. After drying over sodium sulfate, organic layer was evaporated under reduced pressure to get the crude alcohol that was purified by column chromatography (3% methanol in dichloromethane). Yield: 36%

Procedure for Step-5:

To a solution of the alcohol obtained from step-4 (2.3 mmol) in xylene (12 ml) wadded p-toluene sulfonic acid (0.05 eqv) and the resulting reaction mixture was refluxed using a dean-stark apparatus for 5 hrs (monitored by TLC). Reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed successively with saturated sodium bicarbonate solution, water and brine. Organic layer was dried over sodium sulfate evaporated under reduced pressure to get the crude product that was purified by column chromatography (2% methanol in dichloromethane). Yield: 59%

Procedure for Step-6:

A solution of the compound (1.38 mmol) obtained from step-5 was taken in methanol (15 ml) and deoxygenated with argon. To it was added 10% Pd—C (225 mg) and the resulting reaction mixture was hydrogenated under atmospheric pressure for 3 hrs. It was filtered through celite bed, residue washed with methanol and the combined organic layer was evaporated to dryness to get the crude product which was used directly in the next step without any further purification. Yield: 80% (crude)

Preparation of the Amine Building Block A48 3-(Piperidin-1-ylmethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine

Procedure for Step-1:

To a solution of 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (1.0 g, 6.23 mmol) in CH₂Cl₂ (25 mL) were added Et₃N (2.17 mL, 15.57 mmol) and Boc₂O (1.52 mL, 6.54 mmol) and the reaction was stirred at room temperature overnight. The mixture was extracted with aqueous 0.25 M KHSO₄ (50 mL). The organic layer was dried (Na₂SO₄) and evaporated to dryness to afford compound A48-1 (1.29 g, 92%).

Procedure for Step-2:

To a solution of compound A48-1 (1.29 g, 5.75 mmol) in dry THF (50 mL) was added a solution of 2.5 M n-BuLi in hexane (2.53 mL, 6.33 mmol) at −78° C. under argon. After 15 min ethyl formate (702 μL, 8.63 mmol) was added and the reaction mixture was stirred for 15 min at −78° C. Saturated aqueous NH₄Cl (150 mL) was added and the mixture was extracted with CH₂Cl₂ (3×100 mL). The combined organic layer was dried (Na₂SO₄) and evaporated to dryness to afford aldehyde A48-2 (1.21 g, 83%).

Procedure for Step-3:

To a solution of aldehyde A48-2 (1.21 g, 4.80 mmol), piperidine (522 μL, 5.28 mmol) and AcOH (329 μL, 5.76 mmol) in CH₂Cl₂ (50 mL) was added NaBH(OAc)₃ (1.53 g, 7.19 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with CH₂Cl₂ (50 mL) and washed with brine (50 mL). The organic layer was dried (Na₂SO₄) and evaporated to dryness to afford amine A48-3 (1.53 g, 99%).

Procedure for Step-4:

To a solution of compound A48-3 (1.53 g, 4.76 mmol) in CH₂Cl₂ (30 mL) was added TFA (18.3 mL, 238 mmol) and the mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and co-evaporated twice with CH₂Cl₂ (50 mL) to afford amine A48 (3.18 g, ‘302%’).

General Process for Preparing Substituted Sulfonamide Compounds of the Invention:

The carboxylic acids N are converted in an amide formation process using primary or secondary amines O in the presence of water-removing agents such as sodium or magnesium sulfate, phosphorus oxide or reagents such as for example CDI, DCC (optionally polymer-bound), TBTU, EDCI, PyBOP or PFPTFA also in the presence of HOAt or HOBt and an organic base, for example DIPEA or pyridine in an organic solvent such as THF, dichloromethane, diethyl ether, dioxane, DMF or acetonitrile, at temperatures from 0° C. to the reflux temperature, to yield the final products corresponding to formula P.

Parallel Synthesis Methods

Parallel Synthesis Method 1

Acid solution (0.05 M in DCM, 2 ml) was added to 105 μmole of CDI solution (0.105 M in DCM, 1 ml) and shaken for 1 hour at RT. 100 μmole of the amine solution (0.1 M in DCM) were then added at RT and shaken for a further 12 hours at RT. 3 ml of water were next added to the reaction mixture, shaken for 15 minutes, and the organic phase was separated. After distilling of the solvent the crude products were analysed by means of LC-MS and purified by HPLC.

Parallel Synthesis Method 2

EDCI (1.5 equiv.), HOBt (1 equiv.) and diisopropylethylamine (1.5 equiv.) were first of all added to a solution of the corresponding acid (1 equiv.) in DCM (3 ml/mmole) and stirred for 15 minutes at 25° C. The corresponding amine was dissolved in DCM (1 ml/mmole) in another reaction vessel, cooled to 0° C., and diisopropylethylamine (4 equiv.) was added. The cooled solution was added to the acid solution and stirred for 16 hours at RT. For working-up, the mixture was first of all diluted with DCM and then washed in succession with ammonium chloride solution, sodium carbonate solution and saturated NaCl solution, and dried over Na₂SO₄. The solution was concentrated by evaporation to dryness. The product was purified using a purification system from Biotage operating in parallel.

Parallel Synthesis Method 3

-   Stage 1. TFA (20% in DCM, 3 ml/mole) was added at 0° C. to the     Boc-protected amine (1 equiv.). The reaction mixture was heated to     25° C. and stirred at this temperature for 2 hours (DC check). The     solvent was completely removed and the product was carefully dried     in order to remove traces of TFA. The crude product was used without     further purification. -   Stage 2. EDCI (1.5 equiv.), HOBt (1 equiv.) and DIPEA (2.5 equiv.)     were added to a solution of the acid building block (1 equiv.) in     DCM (3 ml/mmole) and stirred for 15 minutes at 25° C. The     Boc-deprotected amine (1.5 equiv.) in DCM (1 ml/mmole) was cooled to     0° C. in another reaction vessel and DIPEA (4 equiv.) was added. The     solution thereby obtained was added to the solution of the acid     building block. The reaction mixture was stirred for 16 hours at     25° C. and then diluted with DCM. The organic phase was washed in     succession with aqueous ammonium chloride solution, aqueous sodium     hydrogen carbonate solution and saturated NaCl solution. The organic     phase was dried over Na₂SO₄ and concentrated by evaporation. The     crude product was purified using a parallel purification system from     Biotage.     Biotage Purification of Library Compounds -   Step-1: Before purification all the crude compounds were analyzed to     get LCMS data of each compound. Thus, it is possible to determine     the polarity of compounds. -   Step-2: Each compound was dissolved in minimum quantity of     dichloromethane and loaded onto a Biotage column (Biotage Si 12+M)     and it was then placed in the 12 channel Biotage Quad-3 parallel     purification system. At a time 12 compounds were purified. -   Step-3: Depending on the polarity of the compound (TLC was used to     determine the eluent) specific solvent mixtures were run in 12     channel Biotage Quad-3 purification system and the fractions were     collected in test tubes. Pure fractions were combined after checking     the TLC of all the fractions. -   Step-4: Combined pure fractions from each column were evaporated     under reduced pressure, transferred to pre-tared glass vials using     acetonitrile as solvent and dried in Speed Vac Thermo explorer to     get dry pure compound. These were then submitted for final analysis.     LCMS Method for Monitoring     1. LC Parameters -   Column=phenomenex GEMINI 5 μm C18 110A (50*4.6 mm) -   U.V wavelength=220 nm, 260 nm -   Shimadzu LC system injection volume=1.00 to 5.00 μl -   (Depending on Concentration) -   Flow rate=1.2 ml/min -   Time Program:

A: 0.05% TFA (pH 2.3)

B: Acetonitrile

TIME MODULE EVENTS PARAMETER 0.01 Pumps % B 10 1.50 Pumps % B 30 3.00 Pumps % B 90 4.00 Pumps % B 90 5.00 Pumps % B 10 5.10 System Controller Stop 2. MS Parameters

-   Scan Type: Q1 MS (Q1) -   Polarity: Positive -   Scan Mode Profile -   Ion Source Turbo Spray -   Source Temperature (at setpoint): 200° C.

Start Stop Time (amu) (amu) (sec) Param Start Stop 100.00 800.00 2.00 CEP 26.51 41.21 Detector Parameters):

-   IS (Ion Spray Voltage): 5500 -   Detector CEM: 2200.0 -   DP (Declustering Potential): 50.00 -   EP (Entrance Potential): 10.00 -   HPLC: Schimadzu Prominance integrated with MS of API 2000 LCMS/MS of     Applied Biosystems, and ELS Detector of Polymer labs (temperature     50° C.)

EXAMPLE 1 N-(2-(2-(6-((dimethylamino)methyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide

CDl (0.2 g, 1.23 mmole) was first added to a solution S3 (0.41 g, 1.18 mmole) in DCM (10 ml) and stirred for 1 hour at RT. The amine A18 (0.3 G, 1.18 mmole) dissolved in DCM (10 ml) was then added at this temperature and stirred for a further 16 hours at RT. After completion of the reaction the mixture was first washed with NH₄Cl solution and then with saturated sodium carbonate solution. The organic phase was dried over Na₂SO₄, filtered, and the solvent was distilled off. The crude product was purified by column chromatography (silica gel, DCM/methanol 98:2). m/z=582.3

EXAMPLE 3 N-(2-(2-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide

-   Stage 1. Oxalyl chloride (3.89 ml, 45.3 mmole) and 2 drops of DMF     were added to a solution of the acid S1 (5.0 g, 15.1 mmole) in DCM     (100 ml). The reaction mixture was stirred overnight at RT. After     completion of the reaction the solvent was evaporated to dryness on     a rotary evaporator. The residue was taken up in DCM and again     evaporated to dryness. This was repeated a further two times. The     crude product was used without further purification. Yield: 5.18 g,     98%. -   Stage 2. Triethylamine (720 μl, 5.18 mmole) and     5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (238     mg, 1.48 mmole) were added to a solution of the acid chloride (518     mg, 1.48 mmole) in DCM (10 ml). The reaction mixture was stirred     overnight at RT. After completion of the reaction the solvent was     removed. Purification was first carried out by column chromatography     (silica gel, DCM→DCM/7 M NH₃ in MeOH, 98:2). The product obtained     was taken up in DCM and washed with aqueous HCl (0.5 M, 10 ml). The     organic phase was dried over Na₂SO₄ and concentrated by evaporation.     Yield: 210 mg, 32%. m/z=437.2

Preparation of 2-(piperidin-1-ylmethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine

-   Stage 1. DMAP (0.75 g, 6.12 mmole) followed by Boc₂O (1.34 g, 6.12     mmole) were added to a solution of the ethyl     5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-carboxylate hydrochloride     (1.09 g, 4.70 mmole) in DCM (100 ml). The reaction mixture was     stirred for 18 hours at RT. Since the reaction had still not gone to     completion, further Boc₂O (0.12 g, 0.53 mmole) was added and the     mixture was again stirred overnight. After completion of the     reaction the reaction mixture was washed with aqueous HCl solution 1     M, 100 ml), and the organic phase was dried over Na₂SO₄ concentrated     by evaporation in vacuo. The crude product was purified by column     chromatography (silica gel, ethyl acetate) (Yield: 300 mg, 21%). -   Stage 2. A solution of 7-tert-butyl     2-ethyl-5,6-dihydroimidazo[1,2-a]pyrazin-2,7(8H)-dicarboxylate (300     mg, 1.02 mmole) in THF (15 ml) was cooled to −78° C. and DIBAL-H (1     M in hexane, 2.0 ml, 2.0 mmole) was slowly added under a N₂     atmosphere. The reaction mixture was stirred for 1 hour at this     temperature and Na₂SO₄×10 H₂O was then added until the evolution of     gas was no longer observed. Further Na₂SO₄×10 H₂O was added,     filtered, and the residue was washed with DCM (25 ml). The filtrate     was concentrated and the crude product obtained (450 mg) was used     without further purification in the next stage. -   Stage 3. The tert-butyl     2-formyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-carboxylate (400 mg,     max. 0.91 mmole) and piperidine (158 μl, 1.59 mmole) were dissolved     in DCM (8 ml) and NaBH(OAc)₃ (506 mg, 2.39 mmole) was added in     portions. The reaction mixture was stirred for 2 hours at RT and     then hydrolysed with satd. sodium hydrogen carbonate solution (25     ml). The phases were separated and the aqueous phase was extracted     again with DCM (25 ml). The combined organic phases were washed with     satd. NaCl solution, dried over Na₂SO₄, and concentrated by     evaporation in vacuo (Yield: 260 mg, 90% over 2 stages). -   Stage 4. TFA (2.83 ml, 36.7 mmole) was added to a solution of the     tert-butyl     2-(piperidin-1-ylmethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-carboxylate     (235 mg, 0.73 mmole) in DCM (10 ml) and stirred for 3-4 hours at RT     (DC check). After completion of the reaction the solvent was first     of all removed, DCM was added, and the reaction mixture was again     concentrated by evaporation to dryness. The product was used without     further purification for further reactions.

EXAMPLE 4 (R)-N-(3-oxo-1-phenyl-3-(2-piperidin-1-ylmethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)propyl)naphthalene-2-sulfonamide

The acid S8 (274 mg, 0.77 mmole) and the amine (0.73 mmole) were dissolved in DCM and cooled to 0° C. HOAt (10.01 mg, 0.07 mmole) diisopropylethylamine (0.64 ml, 3.68 mmole) and EDCI (155 mg, 0.81 mmole) were added at this temperature. The reaction mixture was stirred overnight at RT. After completion of the reaction (DC check) the mixture was diluted with DCM (15 ml) and the organic phase was washed in succession with aqueous KHSO₄ solution (0.5 M, 25 ml), satd. NaHCO₃ solution (25 ml) and satd. NaCl solution (25 ml). The organic phase was then dried over Na₂SO₄ and concentrated. The crude product was purified by column chromatography (firstly silica gel, DCM/7 M NH₃ in MeOH, 9:1, then silica gel, DCM/7 M NH₃ in MeOH, 98:2→9:1). Yield: 105 mg. m/z=557.3

EXAMPLE 2 Preparation of 4-methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(2-piperidin-1-ylmethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethoxy)ethyl)benzenesulfonamide Hydrochloride

The acid S1 (1.68 g, 5.06 mmol), HOAt (69 mg, 0.51 mmole), DIPEA (5.30 ml, 30.4 mmole) and EDCI (1.46 g, 7.59 mmole) were added to a solution of the amine (3.17 g, max. 3.48 mmole) in DCM (50 ml). The reaction mixture was stirred overnight at RT. The mixture was then concentrated by evaporation to dryness. The crude product was purified by column chromatography on silica gel (DCM/7 M NH₃ in methanol, 95:5). The product obtained was taken up in DCM (25 ml) and washed with aqueous HCl (0.1 M, 20 ml). The organic phase was dried over Na₂SO₄ and concentrated. Yield: 210 mg, 11%

Preparation of 3-chloro-2-(piperidin-1-ylmethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine

-   Stage 1. Triethylamine (1.34 ml, 9.58 mmole) and Boc₂O (0.92 g, 4.22     mmole) were added to a solution of the     ethyl-3-chloro-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-carboxylate     hydrochloride (1.02 g, 3.83 mmole) in DCM (100 ml) and stirred for     18 hours at RT. After completion of the reaction (DC check) the     reaction mixture was diluted with DCM and washed with aqueous 0.5 M     KHSO₄ solution (100 ml). The organic phase was dried over Na₂SO₄ and     the solvent was evaporated after filtration. -   Stage 2. A solution of the Boc-protected     ethyl-3-chloro-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-carboxylate     (1.19 g, 3.62 mmole) in THF (25 ml) was cooled to −78° C. and     DIBAL-H (1 M in hexane, 7.24 ml, 7.24 mmole) was slowly added under     a N₂ atmosphere. The reaction mixture was stirred for 1 hour at     −78° C. and hydrolysed with Na₂SO₄×10 H₂O until the evolution of gas     was no longer observed. An excess of Na₂SO₄×10 H₂O was added and the     mixture was then filtered. The solid was washed with DCM (2×25 ml)     and the filtrate was then concentrated by evaporation to dryness.     The crude product obtained was used further without further     purification. -   Stage 3. The aldehyde (720 mg, 2.52 mmole) and piperidine (249 μl,     2.52 mmole) were dissolved in DCM (15 ml) and sodium triacetoxy     boron hydride (822 mg, 3.88 mmole) was added in portions. The     reaction mixture was stirred for 4 hours at RT (LCMS check). The     reaction mixture was hydrolysed with saturated aqueous sodium     hydrogen carbonate solution. The phases were separated and the     aqueous phase was extracted once more with DCM (25 ml). The combined     organic phases were washed with saturated NaCl solution (25 ml),     dried over Na₂SO₄, and concentrated by evaporation to dryness. -   Stage 4. TFA (2.61 ml, 33.8 mmole) was added to a solution of the     Boc-protected amine (240 mg, 0.68 mmole) in DCM (10 ml) and stirred     for 4 hours at RT. After completion of the reaction (DC check) the     reaction mixture was concentrated by evaporation to dryness, taken     up in DCM (20 ml), concentrated by evaporation to dryness, taken up     again in DCM (20 ml) and then concentrated by evaporation to     dryness. The crude product was used further without further     purification.

EXAMPLE 5 Preparation of (R)-N-(3-(3-chloro-2-(piperidin-1-ylmethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-3-oxo-1-phenylpropyl)naphthalene-2-sulfonamide

The acid S8 (264 mg, 0.74 mmole) was dissolved in DCM (10 ml), DIPEA (1.18 ml, 6.75 mmole) was added, and the mixture was cooled to 0° C. HATU (282 mg, 0.74 mmole) and the amine (crude product, max. 0.68 mmole) were added and the mixture stirred overnight at RT (DC check). The reaction mixture was concentrated by evaporation to dryness, and the crude product was purified by column chromatography on silica gel (DCM/7 M NH₃ in methanol, 95:5). The product was taken up in DCM (10 ml) and washed with aqueous NaHCO₃ solution. The organic phase was dried over Na₂SO₄ and concentrated. The product was re-purified via a flash column (silica gel, DCM/methanol, 9:1) Yield: 88 mg, 22% over 2 stages)

EXAMPLE 6 Preparation of N-(2-2-(3-chloro-2-(piperidin-1-ylmethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide

The acid S1 (218 mg, 657 μmole), HOAt (8.9 mg, 66 μmole) DIPEA (573 μl, 3.28 mmole) and EDCI (189 mg, 985 μmole) were added to a solution of the amine (695 mg, max. 722 μmole) in DCM (25 ml) and stirred overnight at RT. The reaction mixture was then concentrated by evaporation to dryness and purified by column chromatography on silica gel (flash, DCM/7 M NH₃ in methanol, 99:1). Yield: 319 mg, 86% over 2 stages.

EXAMPLE No. 162 N-((1R)-3-(1-Ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-3-oxo-1-phenylpropyl)naphthalene-2-sulfonamide

Carboxylic acid S9 (120 mg, 0.338 mmol) and N-ethyl-N′-(3-dimethylamino propyl) carbodiimide hydrochloride (EDCI) (96 mg, 0.507 mmol) were dissolved in CH₂Cl₂ (8 mL). HOBt (49 mg, 0.372 mmol), 1-ethyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine (76 mg, 0.507 mmol) and DIPEA (146 μL, 0.845 mmol) were added and the mixture allowed to stir overnight at room temperature. The reaction mixture was diluted with sat. sodium hydrogen carbonate solution and the aqueous layer extracted with CH₂Cl₂ (2×). The combined organics layers were dried (MgSO₄) and concentrated in vacuo. The crude product was purified by column chromatography (silica, ethylacetate/hexane, 2:1) to afford screening compound 162 (150 mg, 91%).

LC/MS: R_(t)=5.2 min; m/z=488.2 [MH]⁺

EXAMPLE No. 163 4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(3-(piperidin-1-ylmethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)ethoxy)ethyl)benzenesulfonamide

To a solution of amine A48 (795 mg, max. 1.19 mmol), carboxylic acid S1 (394 mg, 1.19 mmol) and DIPEA (1.66 mL, 9.52 mmol) in CH₂Cl₂ (20 mL) was added HATU (498 mg, 1.31 mmol) and the mixture was stirred overnight at room temperature. The mixture was evaporated to dryness and subjected to column chromatography (flash, silica, CH₂Cl₂/(7 M NH₃ in MeOH), 99:1 to 97:3). The product was then purified further by preparative LCMS twice to afford screening compound 163 (35 mg, 5.5%).

EXAMPLE No. 164 (R)-N-(3-oxo-1-phenyl-3-(3-(piperidin-1-ylmethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)propyl)naphthalene-2-sulfonamide

To a solution of amine A48 (1.59 g, max 2.38 mmol), carboxylic acid S9 (846 mg, 2.38 mmol) and DIPEA (3.32 mL, 19.0 mmol) in CH₂Cl₂ (40 mL) was added HATU (995 mg, 2.62 mmol) and the mixture was stirred overnight at room temperature. The mixture was evaporated to dryness and subjected to column chromatography (flash, silica, CH₂Cl₂/(7 M NH₃ in MeOH), 99:1 to 97:3). The product was then purified further by preparative LCMS twice to afford screening compound 164 (28 mg, 2.1%).

The synthesis methods (parallel syntheses) for the example compounds are listed in the following table. The synthesised example compounds (1) to (161) were analysed inter alia according to their molecular weight. The molecular weights measured by means of ESI-MS are summarised in the following table:

Mol. wt. Example Method (ESI-MS) 1 582.3 2 533.3 3 537.2 4 556.3 5 591.2 6 567.2 7 2 534.3 8 2 542.2 9 2 547.28 10 2 558.23 11 2 518.26 12 3 575.77 13 3 599.8 14 1 568.3 15 1 594.3 16 1 608.3 17 1 574.2 18 1 547.3 19 1 568.3 20 1 602.2 21 1 492.2 22 1 597.3 23 1 567.3 24 1 585.3 25 1 573.2 26 1 597.3 27 1 505.3 28 1 463.2 29 1 526.2 30 1 560.2 31 1 555.2 32 1 525.2 33 1 561.2 34 1 553.3 35 1 543.2 36 1 531.2 37 1 593.2 38 1 555.2 39 1 611.2 40 1 539.3 41 1 602.3 42 1 636.2 43 1 526.2 44 1 567.3 45 1 525.2 46 1 512.2 47 1 617.3 48 1 587.3 49 1 615.3 50 1 593.2 51 1 643.3 52 1 491.3 53 1 449.2 54 1 512.2 55 1 546.2 56 1 436.2 57 1 547.2 58 1 539.3 59 1 529.2 60 1 517.2 61 1 579.2 62 1 541.2 63 1 597.2 64 1 567.3 65 1 475.3 66 1 433.2 67 1 496.2 68 1 530.2 69 1 525.2 70 1 495.2 71 1 531.2 72 1 523.3 73 1 513.2 74 1 501.2 75 1 563.2 76 1 525.2 77 1 581.2 78 1 551.3 79 1 505.3 80 1 463.2 81 1 526.2 82 1 560.2 83 1 555.2 84 1 525.2 85 1 561.2 86 1 553.3 87 1 543.2 88 1 531.2 89 1 555.2 90 1 581.3 91 1 624.3 92 1 650.4 93 1 664.4 94 1 666.4 95 1 638.4 96 1 652.4 97 1 604.4 98 1 630.3 99 1 576.3 100 1 519.3 101 1 533.3 102 1 533.3 103 1 533.3 104 1 547.3 105 1 582.3 106 1 608.3 107 1 622.3 108 1 624.3 109 1 596.3 110 1 610.3 111 1 562.3 112 1 588.2 113 1 534.3 114 1 477.2 115 1 491.3 116 1 684.3 117 1 700.3 118 1 672.3 119 1 686.4 120 1 638.4 121 1 664.3 122 1 610.3 123 1 567.3 124 1 567.3 125 1 615.3 126 1 644.3 127 1 670.3 128 1 684.3 129 1 658.3 130 1 650.3 131 1 596.3 132 1 539.3 133 1 539.3 134 1 548.3 135 1 463.2 136 1 477.2 137 1 477.2 138 1 477.2 139 1 552.3 140 1 578.3 141 1 592.3 142 1 594.3 143 1 566.3 144 1 558.2 145 1 504.3 146 1 461.2 147 1 461.2 148 1 553.3 149 1 622.3 150 1 624.3 151 1 596.3 152 1 477.2 153 1 491.3 154 1 553.3 155 1 553.3 156 584.3 157 571.3 158 532.3 159 555.3 160 561.3 161 548.3 Parallel Synthesis Method 4:

-   Procedure for step-1: Boc-protected amine BB (1 eqv) was treated     with 20% TFA in DCM (10 ml/mol) at 0° C. and the resulting reaction     mixture was allowed to stir at 25° C. for 4 hrs (monitored by TLC).     Solvent was completely evaporated, dried properly to remove traces     of TFA and the residue was directly used in library synthesis. -   Procedure for step-2: To a dichloromethane solution (3 ml/mmol) of     acid BBs (1 eqv) was added EDCI (1.5 eqv), HOBT (1 eqv), DIPEA (2.5     eqv) and the resulting reaction mixture was allowed to stir for 15     minutes at 25° C. In another R.B flask, Boc deprotected amine BB     (1.5 eqv) in dichloromethane (1 ml/mmol) was cooled in ice bath,     treated with DIPEA (4 eqv) and it was added to the reaction mixture.     Reaction mixture was allowed to stir at 25° C. for 16 hrs and     diluted with dichloromethane. Organic layer was successively washed     with aqueous ammonium chloride, sodium bicarbonate and brine and     finally dried over sodium sulfate. Evaporation of organic layer     under reduced pressure gave the crude product, which was purified by     Biotage parallel purification system. Yield: 20-25%     Example compounds 165-179 were Obtained by Parallel Synthesis Method     4:

Example No. Structure Name 165

4-Methoxy-N,2,6-trimethyl-N-(2-(2- oxo-2-(6-(pyridin-4-ylmethyl)-3,4- dihydropyrrolo[1,2-a]pyrazin-2(1H)- yl)ethoxy)ethyl)benzenesulfonamide 166

4-Methoxy-N,2,6-trimethyl-N-(2-(2- oxo-2-(6-(pyridin-3-yl)-3,4- dihydropyrrolo[1,2-a]pyrazin-2(1H)- yl)ethoxy)ethyl)benzenesulfonamide 167

N-(3-Oxo-1-phenyl-3-(6-(pyridin-3- yl)-3,4-dihydropyrrolo[1,2- a]pyrazin-2(1H)- yl)propyl)naphthalene-2-sulfonamide 168

N-(3-Oxo-1-phenyl-3-(6-(pyridin-4- yl)-3,4-dihydropyrrolo[1,2- a]pyrazin-2(1H)- yl)propyl)naphthalene-2-sulfonamide 169

N-(3-Oxo-1-phenyl-3-(6-(pyridin-4- ylmethyl)-3,4-dihydropyrrolo[1,2- a]pyrazin-2(1H)- yl)propyl)naphthalene-2-sulfonamide 170

4-Methoxy-N,2,6-trimethyl-N-(2-(2- oxo-2-(6-(2-(pyridin-3-yl)ethyl)-3,4- dihydropyrrolo[1,2-a]pyrazin-2(1H)- yl)ethoxy)ethyl)benzenesulfonamide 171

N-(3-Oxo-1-phenyl-3-(6-(2-(pyridin- 3-yl)ethyl)-3,4-dihydropyrrolo[1,2- a]pyrazin-2(1H)- yl)propyl)naphthalene-2-sulfonamide 172

4-Methoxy-N,2,6-trimethyl-N-(2-(2- oxo-2-(6-(2-(pyridin-4-yl)ethyl)-3,4- dihydropyrrolo[1,2-a]pyrazin-2(1H)- yl)ethoxy)ethyl)benzenesulfonamide 173

N-(3-Oxo-1-phenyl-3-(6-(2-(pyridin- 4-yl)ethyl)-3,4-dihydropyrrolo[1,2- a]pyrazin-2(1H)- yl)propyl)naphthalene-2-sulfonamide 174

4-Methoxy-N,2,6-trimethyl-N-(2-(2- oxo-2-(6-(pyridin-3-ylmethyl)-3,4- dihydropyrrolo[1,2-a]pyrazin-2(1H)- yl)ethoxy)ethyl)benzenesulfonamide 175

4-Methoxy-N,2,6-trimethyl-N-(2-(2- oxo-2-(2-(pyridin-4-yl)-5,6-dihydro- imidazo[1,2-a]pyrazin-7(8H)- yl)ethoxy)ethyl)benzenesulfonamide 176

N-(3-Oxo-1-phenyl-3-(6-(pyridin-3- ylmethyl)-3,4-dihydropyrrolo[1,2- a]pyrazin-2(1H)- yl)propyl)naphthalene-2-sulfonamide 177

4-Methoxy-N,2,6-trimethyl-N-(2-(2- oxo-2-(6-(pyridin-4-yl)-3,4- dihydropyrrolo[1,2-a]pyrazin-2(1H)- yl)ethoxy)ethyl)benzenesulfonamide 178

4-Methoxy-N,2,6-trimethyl-N-(2-(2- oxo-2-(2-(2-(pyridin-4-yl)ethyl)-5,6- dihydroimidazo[1,2-a]pyrazin- 7(8H)- yl)ethoxy)ethyl)benzenesulfonamide 179

4-Methoxy-N,2,6-trimethyl-N-(2-(2- oxo-2-(2-(pyridin-4-ylmethyl)-5,6- dihydroimidazo[1,2-a]pyrazin- 7(8H)- yl)ethoxy)ethyl)benzenesulfonamide The following building blocks were used in the synthesis of example compounds 165-179

Example Amine No. No. Amine Name Acid No. Acid Name 165 A40 6-(Pyridin-4-ylmethyl)- S1 2-(2-(4-Methoxy-N,2,6- 1,2,3,4-tetrahydro- trimethylphenylsulfonamido)ethoxy)acetic pyrrolo[1,2-a]pyrazine acid 166 A42 6-(Pyridin-3-yl)-1,2,3,4- S1 2-(2-(4-Methoxy-N,2,6- tetrahydropyrrolo[1,2- trimethylphenylsulfonamido)ethoxy)acetic a]pyrazine acid 167 A42 6-(Pyridin-3-yl)-1,2,3,4- S8 3-(Naphthalene-2- tetrahydropyrrolo[1,2- sulfonamido)-3- a]pyrazine phenylpropanoic acid 168 A39 6-(Pyridin-4-yl)-1,2,3,4- S8 3-(Naphthalene-2- tetrahydropyrrolo[1,2- sulfonamido)-3- a]pyrazine phenylpropanoic acid 169 A40 6-(Pyridin-4-ylmethyl)- S8 3-(Naphthalene-2- 1,2,3,4-tetrahydro- sulfonamido)-3- pyrrolo[1,2-a]pyrazine phenylpropanoic acid 170 A44 6-(2-(Pyridin-3-yl)ethyl)- S1 2-(2-(4-Methoxy-N,2,6- 1,2,3,4-tetrahydro- trimethylphenylsulfonamido)ethoxy)acetic pyrrolo[1,2-a]pyrazine acid 171 A44 6-(2-(Pyridin-3-yl)ethyl)- S8 3-(Naphthalene-2- 1,2,3,4-tetrahydro- sulfonamido)-3- pyrrolo[1,2-a]pyrazine phenylpropanoic acid 172 A41 6-(2-(Pyridin-4-yl)ethyl)- S1 2-(2-(4-Methoxy-N,2,6- 1,2,3,4-tetrahydro- trimethylphenylsulfonamido)ethoxy)acetic pyrrolo[1,2-a]pyrazine acid 173 A41 6-(2-(Pyridin-4-yl)ethyl)- S8 3-(Naphthalene-2- 1,2,3,4-tetrahydro- sulfonamido)-3- pyrrolo[1,2-a]pyrazine phenylpropanoic acid 174 A43 6-(Pyridin-3-ylmethyl)- S1 2-(2-(4-Methoxy-N,2,6- 1,2,3,4-tetrahydro- trimethylphenylsulfonamido)ethoxy)acetic pyrrolo[1,2-a]pyrazine acid 175 A45 2-(Pyridin-4-yl)-5,6,7,8- S1 2-(2-(4-Methoxy-N,2,6- tetrahydroimidazo[1,2- trimethylphenylsulfonamido)ethoxy)acetic a]pyrazine acid 176 A43 6-(Pyridin-3-ylmethyl)- S8 3-(Naphthalene-2- 1,2,3,4-tetrahydro- sulfonamido)-3- pyrrolo[1,2-a]pyrazine phenylpropanoic acid 177 A39 6-(Pyridin-4-yl)-1,2,3,4- S1 2-(2-(4-Methoxy-N,2,6- tetrahydropyrrolo[1,2- trimethylphenylsulfonamido)ethoxy)acetic a]pyrazine acid 178 A47 2-(2-(Pyridin-4-yl)ethyl)- S1 2-(2-(4-Methoxy-N,2,6- 5,6,7,8-tetrahydro- trimethylphenylsulfonamido)ethoxy)acetic imidazo[1,2-a]pyrazine acid 179 A46 2-(Pyridin-4-ylmethyl)- S1 2-(2-(4-Methoxy-N,2,6- 5,6,7,8-tetrahydro- trimethylphenylsulfonamido)ethoxy)acetic imidazo[1,2-a]pyrazine acid The purity (determined by UV), the ESI-MS Results as well as the retention times are given in the following table:

Purity-UV Example No. [%] MS-Found Rt [min] 165 100.0 527.3 2.791 166 100.0 513.3 2.826 167 100.0 537.3 2.953 168 91.6 537.2 9.649 169 100.0 551.3 2.904 170 100.0 541.2 2.829 171 100.0 565.1 2.938 172 97.2 541.1 2.824 173 100.0 565.4 9.877 174 99.3 527.5 2.823 175 100.0 514.4 2.683 176 95.7 551.3 9.820 177 100.0 513.2 2.791 178 94.2 542.1 2.330 179 98.9 528.2 2.280 Pharmacological Data:

The agonistic and antagonistic action of the compounds according to the invention on the bradykinin 1 receptor (B1R) of humans and rats were determined as described above. Antagonists lead to a suppression of the Ca²⁺ inflow. The % inhibition compared to the maximum achievable inhibition was calculated. The compounds according to the invention are highly effective on the human and rat receptor.

hB1R rB1R [10 μM] [10 μM] % Example % Inhibition Inhibition 1 89 58 2 106 104 3 43 93 4 102 98 5 99 97 6 100 99 7 101 99 8 95 42 9 101 102 10 97 100 11 103 102 12 97 100 13 44 100 14 103 100 15 101 101 16 104 102 17 102 102 18 82 98 19 101 98 20 84 98 21 31 100 22 53 97 23 47 97 24 32 99 25 55 98 26 34 99 27 95 98 28 37 81 29 96 79 30 98 76 31 95 67 32 78 99 33 71 66 34 58 42 35 81 48 36 97 85 37 38 72 38 97 43 39 35 80 40 34 95 41 57 96 42 33 91 43 33 73 44 88 98 45 83 99 46 41 96 47 42 100 48 54 98 49 39 69 50 48 100 51 58 85 52 100 98 53 101 99 54 98 93 55 100 99 56 85 97 57 102 99 58 102 97 59 95 99 60 100 98 61 100 99 62 101 98 63 102 100 64 100 99 65 101 99 66 87 92 67 99 100 68 101 100 69 101 100 70 101 99 71 95 95 72 97 71 73 102 99 74 99 102 75 63 48 76 101 97 77 71 53 78 32 77 79 101 100 80 99 97 81 98 99 82 101 99 83 101 100 84 101 99 85 99 92 86 91 71 87 101 100 88 101 98 89 100 98 90 47 66 91 103 103 92 102 102 93 103 102 94 104 102 95 101 101 96 102 101 97 89 102 98 101 102 99 102 101 100 98 103 101 91 102 102 96 102 103 101 102 104 93 102 105 100 100 106 99 101 107 98 102 108 102 102 109 102 101 110 103 100 111 100 100 112 101 101 113 103 93 114 80 42 115 91 97 116 103 102 117 82 88 118 96 96 119 52 54 120 84 92 121 101 102 122 101 101 123 41 86 124 58 96 125 25 78 126 101 102 127 99 102 128 101 103 129 100 101 130 104 102 131 101 101 132 100 102 133 105 102 134 104 103 135 104 102 136 104 103 137 104 102 138 104 102 139 102 103 140 102 101 141 103 101 142 103 101 143 100 99 144 104 104 145 104 103 146 102 102 147 103 103 148 100 98 149 104 104 150 103 103 151 102 103 152 102 102 153 103 103 154 23 87 155 75 101 162 57 98 163 103 164 102 165 100 99 166 100 99 167 32 70 168 55 57 169 78 98 170 99 98 171 30 99 172 100 97 173 20 75 174 100 94 175 100 102 176 45 87 177 99 97 178 99 100 179 100 100

The foregoing description and examples have been set forth merely to illustrate the invention and are not intended to be limiting. Since modifications of the described embodiments incorporating the spirit and substance of the invention may occur to persons skilled in the art, the invention should be construed broadly to include all variation within the scope of the appended claims and equivalents thereof. 

1. A substituted sulfonamide compound corresponding to formula I

wherein m and n each independently denote 0, 1 or 2; p denotes 1 or 2; Q denotes —O—or —CH₂—; X denotes N or CR⁵; Y denotes N or CR⁶; Z denotes N or CR⁷; R¹denotes phenyl or naphthyl, in each case unsubstituted or mono- or polysubstituted with substituents independently selected from the group consisting of methyl, methoxy, CF₃, F, Cl and Br; R² denotes H, C₁₋₆-alkyl, phenyl or phenyl bonded via a C₁₋₆-alkylene group, wherein phenyl in each case may be unsubstituted or mono- or polysubstituted with identical or different substituents selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, F, Cl Br, I, CF₃, OCF₃ and OH; R³ denotes H or phenyl, wherein phenyl may be unsubstituted or mono- or polysubstituted with identical or different substituents selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, F, Cl Br, I, CF₃, OCF₃ and OH; R⁴ denotes H, C₁₋₆-alkyl, phenyl, naphthyl, pyridinyl, thienyl, furyl, or phenyl, naphthyl, pyridinyl, thienyl, or furyl bonded via a C₁₋₆-alkylene group, C₂₋₆-alkenylene group or C₂₋₆-alkynylene group; wherein phenyl, naphthyl, pyridinyl, thienyl, or furyl in each case may be unsubstituted or mono- or polysubstituted with identical or different substituents selected from the group consisting of O—C₁₋₃-alkyl, unsubstituted C₁₋₆-alkyl, F, Cl, Br, CF₃, OCF₃, OH and SH; R⁵ denotes H; R⁶ denotes H, or a group selected from the group consisting of

wherein R⁸ and R⁹ each denote methyl; j is 1 2 or 3; and one of M¹, M² and M³ denotes N and the other two each denote CH; and R⁷ denotes H, halogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or a group selected from the group consisting of

wherein R⁸ and R⁹ each denote methyl; j is 1 2 or 3; and one of M¹, M² and M³ denotes N and the other two each denote CH; wherein said C₁₋₆-alkyl, C₁₋₆-alkylene, C₂₋₆-alkenylene, and C₂₋₆-alkynylene, each may be unsubstituted or mono- or poly-substituted with identical or different substituents; and said C₁₋₆-alkyl, C₁₋₆-alkylene, C₂₋₆-alkenylene, and C₂₋₆-alkynylene groups each may be branched or unbranched; or a physiologically compatible salt thereof.
 2. A compound as claimed in claim 1, wherein said compound is in the form of an isolated stereoisomer.
 3. A compound as claimed in claim 1, wherein said compound is in the form of a mixture of stereoisomers in any mixing ratio.
 4. A compound as claimed in claim 3, wherein said mixture is a racemic mixture.
 5. A compound as claimed in claim 1, wherein p is
 1. 6. A compound as claimed in claim 1, wherein if Q=—O—, then m and n are each 1, and if Q=—CH₂—, then the sum m+n=0 or
 1. 7. A compound as claimed in claim 1, wherein: X denotes N; Y denotes CR⁶, and Z denotes CR⁷; or X denotes N; Y denotes N, and Z denotes CR⁷; or X denotes CR⁵; Y denotes CR⁶, and Z denotes CR⁷.
 8. A compound selected from the group consisting of: (1) N-(2-(2-(6-((dimethylamino)methyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide, (2) 4-methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(2-(piperidin-1-ylmethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethoxy)ethyl)benzenesulfonamide, (3) N-(2-(2-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide, (4) (R)-N-(3-oxo-1-phenyl-3-(2-(piperidin-1-ylmethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)propyl)naphthalene-2-sulfonamide, (5) (R)-N-(3-(3-chloro-2-(piperidin-1-ylmethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-3-oxo-1-phenylpropyl)naphthalene-2-sulfonamide, (6) N-(2-(2-(3-chloro-2-(piperidin-1-ylmethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide, (7) 4-methoxy-N,2,6-trimethyl-N-(2-(2-(6-(morpholinomethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide, (8) N-(3-oxo-1-phenyl-3-(6-(pyrrolidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)propyl)naphthalene-2-sulfonamide, (9) 4-methoxy-N,2,6-trimethyl-N-(2-(2-(6-((4-methylpiperazin-1-yl)methyl)-3,4-dihydropyrrolo-[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)-ethyl)benzenesulfonamide, (10) N-(3-(6-(morpholinomethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-3-oxo-1-phenylpropyl)naphthalene-2-sulfonamide, (11) 4-methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(6-(pyrrolidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (12) 4-methoxy-N,2,6-trimethyl-N-(2-(2-(6-(3-(4-methylpiperazin-1-yl)propyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide, (13) N-(3-(6-(3-(4-methylpiperazin-1-yl)propyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-3-oxo-1-phenylpropyl)naphthalin-2-sulfonamide, (14) N-(2-(2-(6-((dimethylamino)methyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide, (15) 4-methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(1-phenyl-6-(pyrrolidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (16) 4-methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(1-phenyl-6-(piperidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (17) N-(2-(2-(6-((dimethylamino)methyl)-1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzene-sulfonamide, (18) N-(2-(2-(1-tert-butyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzenesulfonamide, (19) N-isobutyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-oxo-2-(1-(pyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzolsulonamide, (20) N-(2-(2-(1-(6-chloropyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzenesulfonamide, (21) N-(2-(2-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzenesulfonamide, (22) N-isobutyl-4-methoxy-N-(2-(2-(1-(4-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-2,3,6-trimethylbenzenesulfonamide, (23) N-isobutyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-oxo-2-(1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (24) N-(2-(2-(1-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzenesulonamide, (25) N-isobutyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-oxo-2-(1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (26) N-isobutyl-4-methoxy-N-(2-(2-(1-(3-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-2,3,6-trimethylbenzenesulfonamide, (27) N-(2-(2-(1-tert-butyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethylbenzenesulfonamide, (28) 4-methoxy-N,2,3,5-tetramethyl-N-(2-(2-(1-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide, (29) 4-methoxy-N,2,3,5-tetramethyl-N-(2-(2-oxo-2-(1-(pyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (30) N-(2-(2-(1-(6-chloropyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethylbenzenesulfonamide, (31) 4-methoxy-N-(2-(2-(1-(4-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,3,5-tetramethylbenzenesulfonamide, (32) 4-methoxy-N,2,3,5-tetramethyl-N-(2-(2-oxo-2-(1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (33) N-(2-(2-(1-(3,4-difluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethylbenzenesulfonamide, (34) N-(2-(2-(1-(3,4-dimethylphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethylbenzenesulfonamide, (35) N-(2-(2-(1-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethylbenzenesulfonamide, (36) 4-methoxy-N,2,3,5-tetramethyl-N-(2-(2-oxo-2-(1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (37) 4-methoxy-N,2,3,5-tetramethyl-N-(2-(2-oxo-2-(1-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (38) 4-methoxy-N-(2-(2-(1-(3-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,3,5-tetramethylbenzenesulfonamide, (39) N-(2-(2-(1-(2-fluoro-4-(trifluoromethyl)phenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethyl-benzenesulfonamide, (40) N-benzyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-(1-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide, (41) N-benzyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-oxo-2-(1-(pyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (42) N-benzyl-N-(2-(2-(1-(6-chloropyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,3,6-trimethylbenzenesulfonamide, (43) N-benzyl-N-(2-(2-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,3,6-trimethylbenzenesulfonamide, (44) N-benzyl-N-(2-(2-(1-tert-butyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylbenzenesulfonamide, (45) N-benzyl-4-methoxy-2,6-dimethyl-N-(2-(2-(1-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide, (46) N-benzyl-N-(2-(2-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylbenzenesulfonamide, (47) N-benzyl-4-methoxy-N-(2-(2-(1-(4-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-2,6-dimethylbenzenesulfonamide, (48) N-benzyl-4-methoxy-2,6-dimethyl-N-(2-(2-oxo-2-(1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (49) N-benzyl-N-(2-(2-(1-(3,4-dimethylphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylbenzenesulfonamide, (50) N-benzyl-4-methoxy-2,6-dimethyl-N-(2-(2-oxo-2-(1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (51) N-benzyl-N-(2-(2-(1-(4-tert-butylphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylbenzenesulfonamide, (52) N-(2-(2-(1-tert-butyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide, (53) 4-methoxy-N,2,6-trimethyl-N-(2-(2-(1-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide, (54) 4-methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(1-(pyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (55) N-(2-(2-(1-(6-chloropyridin-3-yl)-3,4-dihydropyrrolo-[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide, (56) N-(2-(2-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide, (57) N-(2-(2-(1-(3,4-difluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide, (58) N-(2-(2-(1-(3,4-dimethylphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide, (59) N-(2-(2-(1-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide, (60) 4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (61) 4-methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(1-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (62) 4-methoxy-N-(2-(2-(1-(3-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,6-trimethylbenzenesulfonamide, (63) N-(2-(2-(1-(2-fluoro-4-(trifluoromethyl)phenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzene-sulfonamide, (64) N-(2-(2-(1-(4-tert-butylphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide, (65) N-(2-(2-(1-tert-butyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide, (66) N-2,4,6-tetramethyl-N-(2-(2-(1-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide, (67) N,2,4,6-tetramethyl-N-(2-(2-oxo-2-(1-(pyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (68) N-(2-(2-(1-(6-chloropyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide, (69) N-(2-(2-(1-(4-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide, (70) N,2,4,6-tetramethyl-N-(2-(2-oxo-2-(1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (71) N-(2-(2-(1-(3,4-difluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide, (72) N-(2-(2-(1-(3,4-dimethylphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide, (73) N-(2-(2-(1-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide, (74) N,2,4,6-tetramethyl-N-(2-(2-oxo-2-(1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (75) N,2,4,6-tetramethyl-N-(2-(2-oxo-2-(1-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (76) N-(2-(2-(1-(3-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide, (77) N-(2-(2-(1-(2-fluoro-4-(trifluoromethyl)phenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide, (78) N-(2-(2-(1-(4-tert-butylphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide, (79) N-(2-(2-(1-tert-butyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide, (80) 4-methoxy-N,2,3,6-tetramethyl-N-(2-(2-(1-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide, (81) 4-methoxy-N,2,3,6-tetramethyl-N-(2-(2-oxo-2-(1-(pyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (82) N-(2-(2-(1-(6-chloropyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide, (83) 4-methoxy-N-(2-(2-(1-(4-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,3,6-tetramethylbenzenesulfonamide, (84) 4-methoxy-N,2,3,6-tetramethyl-N-(2-(2-oxo-2-(1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (85) N-(2-(2-(1-(3,4-difluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide, (86) N-(2-(2-(1-(3,4-dimethylphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide, (87) N-(2-(2-(1-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide, (88) 4-methoxy-N,2,3,6-tetramethyl-N-(2-(2-oxo-2-(1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (89) 4-methoxy-N-(2-(2-(1-(3-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,3,6-tetramethylbenzenesulfonamide, (90) N-(2-(2-(1-(4-tert-butylphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide, (91) N-(2-(2-(6-((dimethylamino)methyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzene-sulfonamide, (92) N-isobutyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-oxo-2-(1-phenyl-6-(pyrrolidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzene-sulfonamide, (93) N-isobutyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-oxo-2-(1-phenyl-6-(piperidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzene-sulfonamide, (94) N-isobutyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-(6-(morpholinomethyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2- oxoethoxy)ethyl)benzene-sulfonamide, (95) N-(2-(2-(1-benzyl-6-((dimethylamino)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzene-sulfonamide, (96) N-(2-(2-(6-((dimethylamino)methyl)-1-phenethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzene-sulfonamide, (97) N-(2-(2-(1-butyl-6-((dimethylamino)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzene-sulfonamide, (98) N-(2-(2-(6-((dimethylamino)methyl)-1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethyl-benzenesulfonamide, (99) N-(2-(2-(6-((dimethylamino)methyl)-1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzene-sulfonamide, (100) N-(2-(2-(1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzenesulfonamide, (101) N-isobutyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-oxo-2-(1-propyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (102) N-isobutyl-N-(2-(2-(1-isopropyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,3,6-trimethylbenzenesulfonamide, (103) N-(2-(2-(1-ethyl-6-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzenesulfonamide, (104) N-isobutyl-N-(2-(2-(1-isopropyl-6-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,3,6-trimethylbenzenesulfonamide, (105) N-(2-(2-(6-((dimethylamino)methyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethyl-benzenesulfonamide, (106) 4-methoxy-N,2,3,5-tetramethyl-N-(2-(2-oxo-2-(1-phenyl-6-(pyrrolidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H) -yl)ethoxy)ethyl)benzene-sulfonamide, (107) 4-methoxy-N,2,3,5-tetramethyl-N-(2-(2-oxo-2-(1-phenyl-6-(piperidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzene-sulfonamide, (108) 4-methoxy-N,2,3,5-tetramethyl-N-(2-(2-(6-(morpholinomethyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide, (109) N-(2-(2-(1-benzyl-6-((dimethylamino)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethyl-benzenesulfonamide, (110) N-(2-(2-(6-((dimethylamino)methyl)-1-phenethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethyl-benzenesulfonamide, (111) N-(2-(2-(1-butyl-6-((dimethylamino)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethylbenzenesulfonamide, (112) N-(2-(2-(6-((dimethylamino)methyl)-1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethyl-benzenesulfonamide, (113) N-(2-(2-(6-((dimethylamino)methyl)-1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethylbenzenesulfonamide, (114) N-(2-(2-(1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethylbenzenesulfonamide, (115) 4-methoxy-N,2,3,5-tetramethyl-N-(2-(2-oxo-2-(1-propyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (116) N-benzyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-oxo-2-(1-phenyl-6-(pyrrolidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzene-sulfonamide, (117) N-benzyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-(6-(morpholinomethyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzene-sulfonamide, (118) N-benzyl-N-(2-(2-(1-benzyl-6-((dimethylamino)methyl)-3,4-dihydropyrrolo-[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,3,6-trimethyl-benzenesulfonamide, (119) N-benzyl-N-(2-(2-(6-((dimethylamino)methyl)-1-phenethyl-3,4-dihydropyrrolo-[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,3,6-trimethyl-benzenesulfonamide, (120) N-benzyl-N-(2-(2-(1-butyl-6-((dimethylamino)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)-ethyl)-4-methoxy-2,3,6-trimethylbenzenesulfonamide, (121) N-benzyl-N-(2-(2-(6-((dimethylamino)methyl)-1-(thiophen-2-yl)-3,4-dihydro-pyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,3,6-trimethyl-benzenesulfonamide, (122) N-benzyl-N-(2-(2-(6-((dimethylamino)methyl)-1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethyl)ethyl)-4-methoxy-2,3,6-trimethylbenzene-sulfonamide, (123) N-benzyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-oxo-2-(1-propyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (124) N-benzyl-N-(2-(2-(1-isopropyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,3,6-trimethylbenzenesulfonamide, (125) N-benzyl-4-methoxy-2,6-dimethyl-N-(2-(2-oxo-2-(1-phenethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (126) N-benzyl-N-(2-(2-(6-((dimethylamino)methyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylbenzenesulfonamide, (127) N-benzyl-4-methoxy-2,6-dimethyl-N-(2-(2-oxo-2-(1-phenyl-6-(pyrrolidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (128) N-benzyl-4-methoxy-2,6-dimethyl-N-(2-(2-oxo-2-(1-phenyl-6-(piperidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (129) N-benzyl-N-(2-(2-(1-benzyl-6-((dimethylamino)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2-(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylbenzenesulfonamide, (130) N-benzyl-N-(2-(2-(6-((dimethylamino)methyl)-1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylbenzenesulfonamide, (131) N-benzyl-N-(2-(2-(6-((dimethylamino)methyl)-1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylbenzenesulfonamide, (132) N-benzyl-N-(2-(2-(1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylbenzenesulfonamide, (133) 4-methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(1-phenethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (134) N-(2-(2-(1-butyl-6-((dimethylamino)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide, (135) N-(2-(2-(1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide, (136) 4-methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(1-propyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (137) N-(2-(2-(1-isopropyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide, (138) N-(2-(2-(1-ethyl-6-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide, (139) N-(2-(2-(6-((dimethylamino)methyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide, (140) N,2,4,6-tetramethyl-N-(2-(2-oxo-2-(1-phenyl-6-(pyrrolidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (141) N,2,4,6-tetramethyl-N-(2-(2-oxo-2-(1-phenyl-6-(piperidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (142) N,2,4,6-tetramethyl-N-(2-(2-(6-(morpholinomethyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide, (143) N-(2-(2-(1-benzyl-6-((dimethylamino)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide, (144) N-(2-(2-(6-((dimethylamino)methyl)-1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide, (145) N-(2-(2-(6-((dimethylamino)methyl)-1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide, (146) N,2,4,6-tetramethyl-N-(2-(2-oxo-2-(1-propyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (147) N-(2-(2-(1-isopropyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide, (148) 4-methoxy-N,2,3,6-tetramethyl-N-(2-(2-oxo-2-(1-phenethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (149) 4-methoxy-N,2,3,6-tetramethyl-N-(2-(2-oxo-2-(1-phenyl-6-(piperidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (150) 4-methoxy-N,2,3,6-tetramethyl-N-(2-(2-(6-(morpholinomethyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide, (151) N-(2-(2-(1-benzyl-6-((dimethylamino)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide, (152) N-(2-(2-(1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide, (153) N-(2-(2-(1-isopropyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide, (154) N-benzyl-4-methoxy-2,6-dimethyl-N-(2-(2-oxo-2-(1-propyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (155) N-benzyl-N-(2-(2-(1-isopropyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylbenzenesulfonamide, (156) N-(3-(6-(2-(4-methylpiperazin-1-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-3-oxo-1-phenylpropyl)naphthalin-2-sulfonamide, (157) N-(3-(6-(2-morpholinoethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-3-oxo-1-phenylpropyl)naphthalin-2-sulfonamide, (158) 4-methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(6-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (159) N-(3-oxo-1-phenyl-3-(6-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)propyl)naphthalin-2-sulfonamide, (160) 4-methoxy-N,2,6-trimethyl-N-(2-(2-(6-(2-(4-methylpiperazin-1-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide, (161) 4-methoxy-N,2,6-trimethyl-N-(2-(2-(6-(2-morpholinoethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide, (162) N-((1R)-3-(1-Ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-3-oxo-1-phenylpropyl)naphthalene-2-sulfonamide, (163) 4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(3-(piperidin-1-ylmethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)ethoxy)ethyl)benzenesulfonamide, (164) (R)-N-(3-oxo-1-phenyl-3-(3-(piperidin-1-ylmethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)propyl)naphthalene-2-sulfonamide, (165) 4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(6-(pyridin-4-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (166) 4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(6-(pyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (167) N-(3-Oxo-1-phenyl-3-(6-(pyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)propyl)naphthalene-2-sulfonamide, (168) N-(3-Oxo-1-phenyl-3-(6-(pyridin-4-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)propyl)naphthalene-2-sulfonamide, (169) N-(3-Oxo-1-phenyl-3-(6-(pyridin-4-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)propyl)naphthalene-2-sulfonamide, (170) 4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(6-(2-(pyridin-3-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (171) N-(3-Oxo-1-phenyl-3-(6-(2-(pyridin-3-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)propyl)naphthalene-2-sulfonamide, (172) 4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(6-(2-(pyridin-4-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (173) N-(3-Oxo-1-phenyl-3-(6-(2-(pyridin-4-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)propyl)naphthalene-2-sulfonamide, (174) 4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(6-(pyridin-3-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (175) 4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(2-(pyridin-4-yl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethoxy)ethyl)benzenesulfonamide, (176) N-(3-Oxo-1-phenyl-3-(6-(pyridin-3-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)propyl)naphthalene-2-sulfonamide, (177) 4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(6-(pyridin-4-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide, (178) 4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(2-(2-(pyridin-4-yl)ethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethoxy)ethyl)benzenesulfonamide and (179) 4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(2-(pyridin-4-ylmethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethoxy)ethyl)benzenesulfonamide or a physiologically compatible salt thereof.
 9. A pharmaceutical composition comprising a compound as claimed in claim 1, and at least one pharmaceutically acceptable carrier or auxiliary substance.
 10. A method for preparing a compound as claimed in claim 1, said method comprising reacting a carboxylic acid corresponding to formula N, wherein m, n, Q, R¹, R² and R³ have the respective meanings given in claim 1, with an amine corresponding to formula O, wherein p, R⁴, X, Y and Z have the respective meanings given in claim 1, in accordance with the following reaction scheme:

in the presence of a water-extracting agent, a reagent selected from the group consisting of CDI, DCC, TBTU, EDCI, PyBOP and PFPTFA; HOAt or HOBt; and an organic base in an organic solvent, at a temperature from 0° C. to the reflux temperature, to yield an amide product corresponding to formula P.
 11. A process as claimed in claim 10, wherein said water-extracting agent is sodium or magnesium sulfate or phosphorus oxide; said organic base is diisopropylethyl amine or pyridine, and said organic solvent is selected from the group consisting of tetrahydrofuran, dichloromethane, diethyl ether, dioxane, dimethylformamide, and acetonitrile.
 12. A method of treating pain in a subject, said method comprising administering to said subject a pharmacologically effective amount of a compound as claimed in claim
 1. 13. A method as claimed in claim 12, wherein said pain is acute pain, neuropathic pain or chronic pain. 